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Experimental Biology '99 April 17–21, 1999 Washington, D.C.

This year's meeting of professional research scientists is being developed, sponsored, and coordinated by six organizing societies: The American Physiological Society, American Society for Pharmacology and Experimental Therapeutics, American Society for Nutritional Sciences, American Society for Investigative Pathology, The American Association of Immunologists, and the American Association of Anatomists, as well as various guest societies. More than 10,000 independent scientists will meet to present the newest scientific concepts and experimental results.

Intersociety themes this year are cardiovascular biology; cell injury, inflammation and repair; cellular growth and development; epithelial cell biology; metabolic and disease processes; neurobiology; respiratory biology, and signal transduction and gene regulation.

A sampling of the multidisciplinary sessions appears below. The Program and two issues of abstracts contain considerably more details and are mailed to preregistrants before the meeting. For up-to-date information, visit http://www.faseb.org.

The American Physiological Society

Symposia
Mechanisms of Ischemia Reperfusion: Application of Gene-Targeted Animal Models
Chairs: D.N. Granger and D.J. Lefer

This symposium will summarize some of the latest work on mechanisms of ischemia/reperfusion (I/R) injury. Participants will illustrate how gene-targeted animals are being used to address fundamental mechanistic issues related to cardiovascular disease, describe the variety of quantitative cardiovascular measurements (from myocardial infarct size to leukocyte-endothelial cell adhesion in single vessels) that can be obtained from mutant mice, and address the limitations (e.g., compensatory responses to gene deletion) that are often inherent in the use of gene-targeted animal models. The speakers are active investigators in I/R injury and have published work in this field related to the use of gene-targeted mice. The session should attract scientists interested in the fields of myocardial ischemia, inflammation, immunology, oxygen radical biology, and vascular biology/pathology.

Molecular Approaches to Study Cerebral Circulation: New Insight into Physiology and Pathophysiology
Chairs: F. Faraci and D.W. Busija

Speakers will focus on relatively new approaches to the study of vascular function under physiological and pathophysiological conditions, with an emphasis on studies of the cerebral circulation. The speakers will outline experimental methodologies that are largely molecular in nature and generally represent the state-of-the-art for investigations of vascular function and more traditional methods used to study blood vessels. Some specific approaches that will be addressed include the use of gene-targeted mice and viral-mediated gene transfer as well as the molecular biology of potassium channels. Although the focus of the symposium will be on the cerebral circulation, many of the approaches that will be described are relevant for other vascular beds as well.

Angiotensin in Normal and Abnormal Growth of Cardiovascular Tissue
Chairs: K. Berecek and R. Levi

Among the most important functions of the angiotensin II (Ang II) recently recognized is its ability to be a regulator of normal and abnormal cardiovascular cell proliferation and growth. Ang II participates not only in the development of the heart and blood vessels, but is also involved in long-term regulation of the structure of these organs through direct and indirect growth factor properties. Many of the growth effects of angiotensin II are independent of changes in systemic blood pressure and other hemodynamic and reflex effects. The growth-promoting effects of Ang II have been reported for cardiomyocytes, vascular smooth muscle cells, and cardiac and vascular fibroblasts. How the angiotensin receptor is coupled with cellular growth has not been established with certainty. Participants will address the current status of knowledge on the effect of Ang II on the growth of these cell types, including the effect of angiotensin II on the growth of fibroblasts and connective tissue homeostasis; the effect of the overexpression of angiotensin AT₁ and AT₂ receptor transgenes on growth of cardiac tissue; the interaction between growth factors and angiotensin II in remodeling of vascular smooth muscle; the effect of blocking the renin-angiotensin system on cardiovascular remodeling, and the interaction between nitric oxide and superoxide and Ang II in the growth of cardiovascular tissue. This symposium will complement a session on angiotensin II and cardiovascular remodeling in disease states.

Controversies in Cardiovascular Physiology: What are the Primary Local Determinants of Vascular Tone?
Chair: W. Chilian

Transplantation into the Next Century: Genetic Engineering and Xenotransplantation
Chairs: V. Miller and S. Saddi

This session will focus on the challenges and solutions for improving long-term survival of solid organ transplants in humans. Two major challenges facing solid organ transplantation are accelerated artherosclerotic-like processes of the blood vessels in the transplanted organ and the limited availability of donor organs. The emerging fields of genetic engineering and xenotransplantation (animal organs into humans) provide exciting, new opportunities for collaborations among basic scientists in physiology, immunology, and genetics. Speakers are active in programs of transplantation and genetic engineering. Topics include reviews of clinical challenges of solid organ transplantation, immunology of transplantation, and results of state-of-the-art genetic engineering as applied to transplantation. This is physiological genomics, which may ultimately result in improved patient care.

Role of Plasmalemmal Caveolae in Signal Transduction
Chair: P.W. Shaul

Caveolae are small, plasma membrane invaginations that are present in numerous cell types, including adipocytes, smooth muscle, endothelial and epithelial cells. They were originally studied in relation to their key involvement in the intracellular transport of macromolecules. However, recent evidence indicates that they play a critical role in the compartmentalization of downstream effectors. This symposium will examine the role of caveolae in signal transduction, providing important new information of broad physiologic significance. The aspects of cell signaling that participants will discuss include the role of caveolae in inositide-mediated signal transduction, intracellular calcium homeostasis, endothelial cell nitric oxide production, insulin action, and activation of the ras-raf pathway. As such, this symposium will have wide-ranging appeal to researchers investigating signal transduction in a variety of disciplines.

Families of Sodium-Coupled Transporters
Chair: A. Pajor

Recent advances in molecular cloning and sequencing of cDNAs have identified at least eight different gene families of sodium-coupled organic solute transporters in eukaryotes. Many of the sodium-coupled transporters are expressed in epithelia. Within each family of transporters, there are similarities in protein structure and transport mechanism. This symposium will present the molecular advances in five of the major families of sodium-coupled transporters. Speakers will present a general overview of the family and discuss in more detail their own research on members of that family.

Peripheral and Central Mechanisms of Visceral and Somatic Pain
Chair: R.D. Foreman

Pain is a multifaceted experience that involves sensory localization, motivational-affective behaviors, and autonomic responses. Symposium participants will discuss the peripheral and central processing of noxious information from the skin, muscle, and visceral organs during acute and persistent pain experiences. Cutaneous nociceptors have NMDA, AMPA, and kainate receptors that are activated following intraplantar injection of glutamate. Results of electrophysiological anatomical studies to address how the peripheral glutamaterigic system contributes to acute and persistent pain will be discussed. Changes resulting from nociceptive injury in the peripheral nervous system modulate response characteristics spinal neurons. How nociceptive somatic and visceral afferent information is processed in different spinal segments will be addressed. The spinal cord process integrates and transmits noxious information to the thalamus and other supraspinal structures. Long-term alterations in primate thalamus after the spinal cord in injured will be reviewed. These findings have important implications for the potential long-term thalamic reorganization that may occur with persistent pain. Thalamic information, especially the lateral thalamus, transmits noxious information to somatosensory cortex (SI), and to other areas of the cortex. It will be shown that mechanical stimulation of the skin with brush, pressure, and noxious pinch dramatically increases response characteristics of the nociceptive sensitive neurons of SI after an intradermal injection of capsaicin. In addition, the cutaneous receptive fields of these cells are expanded. Thus, receptive field properties of nociceptive SI neurons can be altered with noxious stimulation. This symposium will offer challenges about neural processing underlying changes that occur during acute and persistent pain.

Angiotensin Receptors and Signaling: Evolution and Perspectives
Chair: H. Nishimura

The renin-angiotensin (ANG) system and ANG receptors appear to have evolved during the early stages of vertebrate evolution, and the principal structure of the ang molecule has been well preserved throughout the phylogenetical scale. In mammals, scientists have elucidated the presence of heterogeneity among ANG receptors by using selective nonpeptide receptor antagonists and subsequent cloning of ANG receptor genes. In primitive vertebrates, ANG receptors appear to be rather nonselective to ANG antagonists, whereas ANG receptors in amphibians (60–65%) and birds (75%) show homology to the AT1 receptor subtype and mediate activation of the phosphatidylinositol hydrolysis/cytosolic Ca²⁺ signaling pathway. In addition, an unidentified ANG receptor subtype(s) appears to exist in nonmammalian tissues, and phenotypic changes in the receptor/signaling mechanism occur during development/maturation. Furthermore, the definition of receptor subtypes by using pharmacological tools is not applicable in nonmammalian ANG receptors. Questions that will be discussed: 1) When did the evolution of ligand recognition in ANG receptors occur? Did the evolution of specific ligands require the evolution of specific receptors? 2) Which molecular features preserved among various vertebrate receptors are due to conservation of function, and which divergent features reflect structural adaptation to new function? 3) What are the phenotypic modulations of ANG receptor properties and signaling during development/maturation processes? Recent advancements in these subjects will be presented in multidisciplinary aspects relating molecular/cellular information to intact tissue and organ levels by using various vertebrate animal models. The symposium will appeal to graduate students, postdoctoral fellows, and established investigators in various comparative and general physiology disciplines.

Postmenopausal Physiology
Chair: J. Cannon

Menopause has important consequences for women's health, including increased susceptibility to vascular diseases, thermoregulatory abnormalities (hot flashes), and increased bone resorption, leading to osteoporosis. Menopause has often been ascribed to depletion of a nonrenewable population of follicles, causing diminished production of estradiol. As a result, much of the research and therapy directed at menopause has centered on the issue of ovarian estradiol withdrawal. Although important, focusing on this one aspect of menopause results in both conceptual and clinical problems. For example, it is unclear why the rate of follicle loss increases in middle-aged women and whether the signal(s) for this accelerated loss originated within the ovarian tissue itself. As another example, vascular and skeletal deterioration have been ascribed to cytokine-mediated inflammatory processes that are no longer held in check by the antiinflammatory actions of estradiol, yet proinflammatory factors driving such conditions have not been identified. This symposium will address questions less tightly bound to the ovary/estradiol paradigm: Do menopausal triggers originate in the central nervous system? Are gonadotropins important inducers of inflammatory cytokines? Are these cytokines involved in the altered thermoregulation after menopause? Does exercise training provide cardiovascular or osteogenic benefits to postmenopausal women? This symposium is designed to be more inclusive of younger investigators, with invited speakers ranging from postdoctoral fellows to a department chair.

Advances in the Characterization of N_a⁺- H⁺ Exchanger (NHE) Isoforms
Chairs: P. Aronson and M. Donowitz

Na⁺-H⁺ exchangers are widely expressed in many cell types and participate in a number of important physiologic functions including the regulation of cell pH, the regulation of cell volume, and transepithelial acid-base and N_aC1 transport. The identification of N_a⁺-H⁺ exchanger (NHE) isoforms by molecular cloning techniques opened a new era in the study of this major class of transporter proteins. The use of genetic and immunocytochemical techniques has provided new insight into the function and regulation of NHE isoforms not only at the molecular and cellular level, but also at the integrative level of whole organ physiology. This symposium will summarize recent advances in the characterization of NHE isoforms that have resulted from these technical developments. Participants will specifically discuss the mutual interactions between the ubiquitously expressed housekeeping N_a⁺-H⁺ exchanger isoform (NHE1) and the cytoskeleton, an issue of general relevance to cell physiology; the critical role of adapter proteins in mediating the regulation of an epithelial N_a⁺-H⁺ exchanger isoform (NHE3) by protein kinases; evidence that the renal brush border NHE3 is regulated by membrane trafficking as part of the kidney's response to metabolic acidosis, and the expected and unexpected phenotypes resulting from targeted disruption of NHE isoform genes. The symposium should interest cell, epithelial, gastrointestinal, and renal physiologists and be of general relevance to physiologists interested in the application of molecular tools to the study of problems in integrative physiology.

Glucagon-like Peptide (GLP) 2: Intestinal Growth Factor and Regulatory Peptide
Chair: C. Cheeseman

Intestinal endocrine L-cells produce two peptides related to pancreatic glucagon, glucagon-like peptide1 (GLP-1) and glucagon-like peptide 2 (GLP-2). All three peptides are produced from the same large pro-peptide coded for by single gene. The differential cleavage of the pro-peptide is achieved by two different peptidases and it is their tissue-specific expression that determines the peptide to be subsequently released. GLP-1 is known to have an insulinotropic action on pancreatic B-cells, and its receptor has been cloned. In contrast, in the absence of a receptor for GLP-2 nothing was known about its possible physiological actions, although it is released from L-cells in the small intestinal epithelium into the circulation. It has been shown recently that GLP-2 specifically promotes growth and expression of hexose transporter proteins in the GI tract when plasma levels are elevated for several days in vivo, and that circulating levels of this peptide are elevated in experimental diabetes. Thus it may play a role in the intestinal hypertrophy and increase hexose absorptive capacity known to occur in this disease. The receptor has now been cloned, which should rapidly advance our understanding of the actions of this peptide. Along with the chronic effects of GLP-2, it has been shown that specific acute effects on the small intestine promote hexose absorption. Additional sodium-dependent hexose transporter, SGLT-1 is inserted into the enterocyle brush-border membrane when plasma levels of GLP-2 are elevated in vivo. At the same time, the transporter activity of the facilitated transporter GLUT2 in the basolateral membrane is also increased, so the net effect is to up-regulate glucose absorption. This symposium will look at the physiological roles of GLP-2 in controlling the small intestine in health and disease.

Experimental Physiology in the Polar Regions: The Historical Development
Chairs: G.E. Folk, Jr. and R. Elsner

The American Physiological Society has not attended to the effects of hostile physical environments, except those of high altitude as championed by John B. West. The polar region produces the most extreme environments, with winds of 200 mph and temperatures as low as -125 F. Thus physiological measurements made on humans and lower animals must be designed differently from those made in the university research laboratory, because of the cold and the need for studies under the ice-bound polar waters. What special homeostatic mechanisms and adaptations are to be found in humans living in Siberia and subhuman animals diving for food to 5100 feet at the edge of the polar ice? The history of polar physiology began with simple measurements of anatomy, oxygen consumption, and tissue temperatures. Participants will trace the history of change from these simple measurements to today's sophisticated technology. Specifically, presenters will discuss breeding birds that tolerate the most extreme environment of any breeding species; the history of learning physiology from the exploitation of whales; the importance of experiments in 1950 by Scholander and his influence on physical science of today; how some small mammals combat cold outside their burrows of -55 F by super-cooling their blood, and compression hyperoxia, hypercapnia, and intriogen narcosis during diving of seals.

Comparative Mechanisms to Survive Brain Anoxia: Mitochondria to Organism
Chair: P. Lutz

The last decade has seen explosive developments in our understanding of how animals respond to limiting availability of oxygen, with particular attention on the most vulnerable organ, the brain. While most research, being health oriented, is involved with hypoxia sensitive systems, particularly interesting information is coming from studies of the molecular and metabolic defense mechanisms used by species that are naturally tolerant to anoxia. This symposium will not only present and integrate current views in the field, but will also provide a forum for communication between two large but semi-independent groups of researchers on brain hypoxia, the mammalian/clinical and the comparative. Some of the most promising advances in this field include identifying universal oxygen sensing and signal transduction pathways. Speakers will offer evidence for the involvement of mitochondrial molecular oxygen in an inhibitory signal for protein synthesis; present new findings concerning protective gene activation in hypoxic tolerant cell; compare the anoxia survival mechanisms of the turtle to switch down brain metabolic processed to `idle' and the extraordinary strategy adopted by the frog for slow apoptosis; contrast these strategies with those of the anoxic tolerant carp, which manages to survive anoxia while maintaining locomotory control and sensory function, and discuss and compare the physiological mechanisms that give the mammalian neonate greatly enhanced oxygen tolerance compared to the adult, in particular the role of the adenosine mediated NMDA receptor complex. These presentations are expected to stimulate intellectual exchange and new perspectives on brain hypoxia defense mechanisms.

Effect of Cardiovascular Disease on the Structure and Function of Skeletal Muscle
Chairs: R.C. Carlsen and S.D. Gray

Skeletal muscle plays an important role in maintaining whole body electrolyte and energy homeostasis, so it is not surprising that disorders of the cardiovascular system may give rise to changes in skeletal muscle structure and function. This symposium will focus on the relationship between two cardiovascular disorders and observed changes in skeletal muscle blood flow, energy metabolism, and electrolyte balance. Topics will include the relationship between cardiac insufficiency, a decrease in the concentration of Na+,K+ -pumps in skeletal muscle and alterations in muscle contractile function; changes in blood flow, resistance to fatigue and electrolyte balance in skeletal muscles in spontaneously hypertensive rats, and changes in skeletal muscle function in the heart failure model used in his laboratory. The physiology of skeletal muscle has received little attention in investigations of cardiovascular disease, yet muscle may play a major role in modulating the course of the disease and the therapeutic interventions designed to treat the disease. This session will interest investigators in cardiovascular physiology, exercise physiology, and muscle physiology, and will offer insight into mechanisms associated with muscle fatigue and electrolyte homeostasis.

Physiological Basis of Congestive Heart Failure
Chair: S.R. Houser

Congestive heart failure is the leading cause of death in the United States. Participants will discuss the changes in the physiological phenotype of the failing cardiac myocyte–changes thought to contribute to, cause, or exacerbate heart failure. This symposium will focus on functional derangements in common forms of heart failure rather than in rare genetic forms, including the factors responsible for the characteristics in chamber and myocyte size and shape; the basis of systolic and diastolic pump malfunction in heart failure; the cellular basis of contractile abnormalities in heart failure; the cellular and molecular basis of action potential abnormalities in heart failure, and cytokines as negative inotropic agents in heart failure.

Endothelin and the Central and Peripheral Nervous System
Chairs: D.H. Damon and C. Hinojosa-Laborde

Endothelin is a peptide that was originally identified as a vascular endothelial-derived vasoconstrictor. It is now recognized as being produced by and modulating the function of many organ systems including the central and peripheral nervous system. Although we know that endothelin is expressed by and acts on neuronal and non-neuronal cells in the nervous system, the physiological significance of these observations has not been clearly established. Participants hope to elucidate the physiological importance of endothelin in the nervous system, multiple aspects of endothelin and central and peripheral neuronal function, and consider the role of endothelin in the development of the enteric nervous system, in central control of respiration and cardiovascular function, and in adrenal and in postganglionic sympathetic neuronal function.

Molecular Physiology of Urea Transporters
Chairs: R. Gunn and J. Sands

During the past decade, tremendous progress on the molecular physiology of urea transport proteins has been made possible by the physiologic and biophysical characterization of the vasopressin-regulated urea transporter in the kidney collecting duct, the expression cloning of its cDNA by using Xenopus oocytes, and the preparation of polyclonal antibodies recognizing this protein. This symposium will bring together scientists working on cloning urea transporters with those using these new molecular probes to work on key integrative issues in urea transport. Presenters will discuss recent progress in cloning new urea transporters–the mRNA isoforms and genomic organization of the vasopressin-regulated urea transporter and a new, broad selectivity neutral solute solvent channel. Speakers also will address progress involving functional and integrative issues in urea transport: immunochemical mapping of urea transporters in the kidney using new antibodies the proteins and cell responses to hyperosmolality: from apoptosis to urea transporter induction. Also discussed will be integrative aspects of urea transport in rats– studies of the regulation of rat urea transporters in vivo. The symposium is designed to present the latest research on urea transporters from the gene to the rat.

Phosphodiesterases in Renal Physiology and Pathophysiology
Chairs: M. Humphreys and T. Dousa

Phosphodiesterases (PDEs) are a large family of enzymes that participate in cell signaling by catabolizing intracellular cyclic nucleotide second messengers. Because of their role in regulating cyclic nucleotide levels, they have been targets of pharmacologic intervention in diseases such as asthma and congestive heart failure. The role of PDEs in renal physiology and pathophysiology is less well appreciated. This symposium presents current information on the PDE family with particular emphasis on renal PDEs by experts in the field. Presentations will include an overview of the classification, characteristics, and distribution of the PDE family; the role of PDE isoforms in regulating intracellular cAMP and signaling via the adenylate cyclasse-protein kinase A pathway; data on the roles of PDE3 and PDE4 in mesangial cell growth and proliferation through the regulation of intracellular cAMP; evidence implicating heightened activity of PDEs as the mediator of resistance to the renal actions of atrial naturetic peptide in edema-forming conditions, and data showing a role of PDEs in the regulation of renin secretion. In aggregate, these talks will provide background understanding of the PDE family and specific examples of the function of various family members in regulation kidney function in health and disease.

Asymmetry of Receptor Signaling in Epithelial Cells
Chairs: K. Amsler and P. Wilson

Speakers will introduce the concept that signaling from membrane receptors in polarized epithelia can be influenced by receptor location. They will address the localized nature of receptor signaling phenomena; asymmetric responses initiated upon activation of receptors localized to the apical and basolateral membranes, and changes in receptor localization that occur during renal development and disease. Work on several epithelial systems will be presented, including renal, intestinal, and airway epithelia, demonstrating the potential broad applicability of this concept.

Time Domains of Hypoxic Ventilatory Response: Adaptive Mechanisms in Short- and Long-Term Responses
Chairs: T.E. Dick and G.S. Mitchell

Hypoxia elicits an immediate response from the cardiorespiratory system mediated by the central nervous system. The carotid body senses hypoxemia and its fibers project to the medulla. Activation of these fibers increases blood pressure and ventilation. Recent studies have shown that the ventilatory response to hypoxia has multiple time domains. This symposium will define the various time domains of the hypoxic response, will present data from diverse laboratories regarding the neural substrates and mechanisms involved in these different time domain, and will integrate these mechanisms in the understanding of the hypoxic response of humans. The various time domains are short-term potentiation of ventilation reflects a progressive increase in the amplitude of phrenic activity, short-term depression of ventilation reflects progressive decrease in the frequency of phrenic bursts, and long-term effects have been observed primarily in amplitude of phrenic nerve activity following repetitive hypoxic exposures, and neonatal exposures to hyperoxia lead to long-term changes in the structure of the chemoafferents. Finally, chronic repetitive brief exposures occur in sleep apneics and sensitize them to hypoxia. Participants will also describe the role of the ventrolateral pons in short-term alterations in breathing frequency that follow brief exposures to hypoxia; characterize the role of structures in the rostral ventrolateral medulla that mediate the short-term increases in sympathetic and phrenic nerve activities and an increase in the respiratory-modulation of sympathetic nerve activity; review the role of the Raphe nuclei in mediating long-term facilitation of phrenic nerve activity that develops after repeated hypoxic exposures, specifically examining the reconfiguration of the neural circuit generating the respiratory pattern during long-term facilitation; describe long-term alterations in response to hypoxia due to plasticity of the developing nervous system, and integrate this information to interpret findings that the ventilatory response as well as the sympathetic nerve activity of sleep apneic patients have increased sensitivity to hypoxia. This symposium will clarify the complexity of the response to hypoxia, defining the different time domains in which the response occurs, identifying neural mechanism involved in these responses, and specifying adaptive changes.

Redox Regulation of Gene Expression in Hypoxia
Chairs: M.N. Gillespie and B.A. Freeman

Two rapidly emerging research areas affect the mechanisms underlying hypoxic regulation of gene expression. The first pertains to whether hypoxia evokes changes in cellular redox state, and there is evidence both for and against this possibility. The second concerns the growing recognition that reactive oxygen species function as second messengers in signal transduction, acting to govern gene expression among other cellular activities. This symposium will encourage debate and discussion on the hypothesis that gene expression in lung cells, responsible for the adaptive response of the pulmonary circulation to chronic hypoxia, is mediated by changes in pulmonary vascular cell redox state.

Mechanisms Involved in Hypoxic Pulmonary Vasoconstriction: Can Everyone be Right?
Chairs: E.K. Weir and K.K. Griendling

Considerable work has been done recently on the mechanisms by which hypoxia is sensed and transduced into vasoconstriction in the pulmonary vasculature; however, there is no unanimity as to how this is achieved. A symposium encouraging debate and discussion will help to reach consensus, or define the questions requiring further work.

A. Clifford Barger Memorial Symposium: Genetic Mechanisms Determining the Role of the Kidney in the Pathogenesis of Hypertension
Chairs: R.J. Roman and J.P. Granger

Rapid advances in molecular genetics have led to the search for genes determining the development of hypertension and hypertension associated renal disease in man and genetic animal models. These efforts have already led to the identification of several mutations in renal epithelial transport genes that alter arterial pressure in man and the discovery of a large number of chromosomal regions in animal models that contribute to the development hypertension. Moreover, in the last 2 years investigators have transferred the regions of the genome of interest onto fixed generic backgrounds to create new monogenic animal models of hypertension and have begun to explore the mechanisms involved. Others have developed renal specific promoters to overexpress or knockout genes of interest for hypothesis testing. This symposium will concentrate on the most recent evidence regarding the mechanisms by which various genes alter renal function and/or the renal handling of salt and water and blood pressure in man and these new animal models. Discussion will include work describing the mechanisms by with inherited mutations in renal sodium transporters lead to abnormalities in blood pressure control in man; pioneering work on the development of congenic strains of Dahl S rats harboring chromosomal regions that lower blood pressure; conditional, renal specific promoter, which allows investigators for the first time to create transgenic mice that can be induced to overexprss genes of interest in the kidney for hypothesis testing; renal transplantation studies between congenic strains of normotensive and hypertensive rats that indicate the there are independent genes that determine the susceptibility of animals to develop hypertensive renal injury, and work to identify the genes and mechanisms underlying the development of hypertension and glomerular disease in congenic strains of Fawn Hooded rats.

Biomaterial Design
Chair: D.A. Hammer

This symposium will focus on the molecular design of biomaterials that elicit molecular and cellular functional responses. Our understanding of the physical chemistry of biological molecules, and the structural basis of bio-recognition–key to control of specific biological functions–allows us to now design molecules and biomaterials with tailored physical properties, controllable features of self-assembly, and which elicit a tailored cellular response. Such materials are essential for the emerging technologies of gene therapy, drug delivery, and tissue engineering. The design and synthesis involves either synthetic chemistry or recombinant molecular biology. Participants will discuss recombinant design of carbohydrate-binding lectins, starting with a structural knowledge of carbohydrate recognition; synthetic and recombinant techniques for engineering molecular recognition using proteins and polymers; de novo protein design of channels and membrane fusion machines from a structural knowledge of how these proteins work; the production of self-assembled protein structure and materials that support cell adhesion using recombinant synthesis; the activity of cells on well defined, micropatterned surfaces created with lithographic techniques, which elicit novel cell responses such as angiogenesis and cell proliferation, and the design of complex, vesicle-based carrier for drug delivery of chemotherapeutic agents.

Mechanotransduction
Chair: G.A. Truskey

Mechanotransduction represents the process by which a physical force is translated into a biochemical or biological response. Cells and tissues respond to physical forces such as pressure, fluid shear stresses, and mechanical strain. In the cardiovascular system, physical forces play a significant role in normal function and in disease states such as atherosclerosis, restenosis, and heart failure. Shortly after application of a physical force second messengers are generated. Longer term, physical forces affect protein synthesis, cell replication, mechanical properties of cells and cell shape. Two major unanswered questions in the field are the actual mechanism by which the physical forces are translated into a biochemical signal and whether the cells respond directly to the force and/or gradients in the force. Possible mechanisms for mechanotransduction, alone or in combination, include stretch-activated ion channels, focal adhesions complexes, and the cytoskeleton. Force gradients may produce a differential response by the cell leading to directional changes observed after application of fluid shear stress and mechanical stretch. This symposium will summarize evidence to support these various mechanisms and the presentation of new results from major researches and promising young investigators in the field.

Antioxidants and Oxidative Stress in Health and Disease
Chairs: R. Knopp and T.M. Bray

`Oxidative stress' implies a disturbance in the balance of prooxidant–antioxidant in biological system. Much experimental evidence has demonstrated that tissue specific oxidative stress forms the basis of a diverse number of pathophysiological phenomena leading to diseases such as diabetes, cancer, cardiovascular disease, and neurodegerative disorders. The mechanisms by which free radicals cause disease go beyond the simple chemical oxidation reactions of macromolecules; it is also linked to the gene expression of oxidative stress response element and other specific cellular functions. The function of antioxidant nutrients also reaches molecular and genetic levels. Research involving the interaction of antioxidants, oxidative stress and disease processes is truly an interdisciplinary field that interfaces nutrition and contemporary biology. This interdisciplinary symposium will be an excellent platform for biologists to focus on the molecular and cellular mechanisms by which oxidative stress causes tissue-specific damage and the scientific evidence of the efficacy of antioxidants in preventing diseases.

Beyond Chemotherapy: The Scientific Bases for New Cancer Treatments
Chair: P.H. Wiernik

This review of emerging treatment concepts for neoplastic diseases will include discussions on cytokine treatment of certain solid tumors, such as renal cell carcinoma and malignant melanoma; growth factor stimulation of bone marrow recovery after cytotoxic chemotherapy; induction of maturation and differentiation for certain leukemias with retinoids, arsenic trioxide, and other agents; vaccine treatment of common cancers such as colon cancer, and monoclonal antibody treatment of leukemias and lymphomas. The scientific basis for these new therapeutic modalities as well as current results will be stressed. Presenters will summarize results of current cancer treatment with standard therapy for a variety of neoplasms and prospects for greater success in the near future.

HIV Vaccine Development: Opportunities and Challenges
Chair: M.B. Feinberg

The development of a safe and effective HIV vaccine remains the best hope for containing the continuing spread of the AIDS epidemic; yet, fundamental biological and practical challenges have long frustrated realization of this goal. HIV establishes a chronic infection that destroys essential immune effector functions and cannot be cleared by natural immune responses. As such, HIV infection is fundamentally different from any infectious disease that currently can be prevented by vaccination. Recent insights into central virologic and immunologic aspects of HIV disease, however, have enabled new, more rigorous approaches for the study and development of novel HIV vaccine strategies. This symposium will summarize critical recent research findings from basic and applied HIV vaccine research efforts. The major obstacles to HIV vaccine development and testing will be presented so as to familiarize the audience with current prospects for and future directions of HIV vaccine development efforts.

Translational Research in Psychiatry: From Molecular Medicine to Clinical Practice
Chair: J. Licinio

This symposium will cover the broad applicability of various areas of neuroscience research to psychiatric disorders. Recent progress in basic neuroscience, molecular genetics, pharmacology, neurophysiology, imaging, and clinical investigation has contributed to a new generation of studies aimed to identify the fundamental biology underlying psychiatric disorders. Translational research that brings to the bedside the latest developments in neuroscience is limited by the lack of adequate animal models for the major psychiatric disorders, such as schizophrenia and depression. Nevertheless, the biological components that contribute to specific elements of those disorders can be assessed in the laboratory and in the clinic. The knowledge to be gained should enhance our understanding of brain circuitries and specific candidate systems that underlie the complexity of psychiatric disorders. We will comment on the progress and limitations of dissecting molecular elements that underlie complex disorders that have not only biological, but also psychosocial components, such as psychiatric disorders.

The Road to Apoptosis: Indictment, Judgment, Execution, and Reprieve
Chairs: S. Gupta and V. Dixit

There is only one way to conceive but several ways to die. The process of physiological cell death (apoptosis) can be triggered by diverse signals; however, a relatively limited number of intracellular processes appears to be involved in the regulation or execution of an apoptotic program, which ensures that a cell will die and its corpse will be cleared rapidly without an inflammatory response. Rapid progress in understanding various processes that regulate apoptosis has led to understanding the pathogenesis of certain diseases in experimental animals and humans. This symposium will examine various facets of apoptosis ranging from the initial signals to the cell executioners. Participants will discuss the signals and receptors that trigger apoptosis, the Bc1–2 family of proteins that play an important role in controlling the pathways of apoptosis, and downstream pathways including caspases and the role of mitochondria.

Regulation of Cellular Processes by Infectious Microbes
Chair: C.E. McCall

The interaction of microbes with host cells dictates the type and degree of infectious diseases. Gene products of microbes have evolved to interact specifically with host cells in a fashion designed to favor microbial infection over host defense. Specific gene products of microbes or constituents of their anatomy that act on host cell elements are now being identified, and the mechanism by which they alter host cells characterized. Examples of microbial products include bacterial endotoxin, bacterial super antigens, and specific gene products. Mechanisms include alterations in apoptosis, intracellular metabolism, anatomy, cell growth and differentiation, and induction and repression of genes. This session will present data on the pathobiologic reactions between microbes and host cells that may define the outcome of any given infectious disease.

Hormonal Control of Protein Metabolism in Muscle
Chair: R.R. Wolfe

The focus of this symposium will be the nutritional and hormonal control of muscle metabolism. Talks will cover physiological control mechanisms, as well as regulation at the molecular level. Particular attention will be given to the influence of amino acid intake and the mechanism of action of insulin and insulin-like growth factor 1 on protein anabolism. Also, the mediators of protein breakdown in catabolic states will be covered.

Transplantation into the Next Century: Genetic Engineering and Xenotransplantation
Chairs: V. Miller and S. Saddi

This session will focus on the challenges and solutions for improving long-term survival of solid organ transplants in humans. Two major challenges facing solid organ transplantation are accelerated artherosclerotic-like processes of the blood vessels in the transplanted organ and the limited availability of donor organs. The emerging fields of genetic engineering and xenotransplantation (animal organs into humans) provide exciting, new opportunities for collaborations among basic scientists in physiology, immunology, and genetics to address these challenges. Topics will include reviews of clinical challenges of solid organ transplantation, immunology of transplantation, and results of state-of-the-art genetic engineering as applied to transplantation. This is `physiological genomics', which may ultimately result in improved patient care.

Secretion: Mechanisms and Regulation of Exocytosis
Chairs: B.H. Hirst and D.A. Eisner

Keynote Lecture: The minimal machinery for vesicle budding and fusion

The molecular mechanics of single proteins observed by atomic force microscopy

The fusion complex of exocytosis and enveloped viral fusion

Regulation of synaptic vesicle exocytosis

Reformation of vesicles after exocytosis

Molecular mechanisms of neurotransmitter release: A functional view

Neurosecretion competence: an independently regulated trait of the neurosecretory cell phenotype

Stimulation of exocytosis without a calcium signal

Neuroendocrine Determinants of Obesity and Satiety
Chair: J.F. Caro

Microcirculatory Studies of Inflammation and Immune Function
Chair: R.F. Tuma

Physiology InFocus: Genomics and Molecular Medicine
Physiological Genomics: Launching a New Journal

Chair: V. Dzau

Physiological Genomics: What Does it Mean?

Normal Vectors for Gene Therapy

The Molecular Biology and Genomics of Heparan Bosynthetic Enzymes and their Role in Health and Disease

Role of Physiology in the Hunt for Genes of Hypertension

Tissue-Specific Gene Targeting as a Window into Physiological Function
Chairs: L.G. Navar and C.D. Sigmund

Manipulation of the Mouse Genome to Study Renal Mechanisms in Hypertension

Genetic Control of Cardiac Hypertrophy

Regulation and Mechanism of Synaptic Plasticity Studied with Genetically Engineered Mice

Surgical Manipulation of the Genome by Cre-Recombinase

From Genome to Function
Chair: S. Gullans

Sequencing of genomes

Protein-protein interactions and yeast: two hybrid systems.

Analysis of protein expression.

cDNA arrays to define biological pathways.

Secrets of the Sarcomere Revealed by Transgenesis and Gene Transfer
Chairs: J.M. Metzger and R.J. Solaro

This symposium focuses on the mysteries of the sarcomere, the functionsl unit of striated muscle. The sarcomere consists of literally hundreds of different protein subunits that are exquisitely packaged into a near-crystalline lattice array of filaments. A major challenge is to understand the function of individual molecules of the sarcomere within context of the intact cell. The control of sarcomere function begins with Ca2⁺-mediated regulatory events, and ends with a chemomechanical transduction event involving the docking of the molecular assembly, it can then be appreciated that the control and regulation of sarcomeric function arsenal of genetic-based tools, in concert with technological advances in functional assays, organ levels. This symposium will highlight these advances, including recent studies employing transgenesis, mutagenesis, gene targeting, and viral-based somatic cell gene transfer, to reveal some of the long-held secrets of the sarcomere.

Lectureships

Robert M. Berne Distinguished Lectureship of the APS Cardiovascular Section
Speaker: B.R. Duling

Vessel-to-vessel signaling in resistance vessels: who's talking, who's listening?

August Krogh Distinguished Lectureship of the APS Comparative Physiology Section
Living Without Oxygen: Lessons from the Freshwater Turtle

Speaker: D. C. Jackson

Edward F. Adolph Distinguished Lectureship of the APS Environmental & Exercise Physiology Section
Blood Volume Regulation: Hierarchical Solutions to Environmental Challenges

Speaker: E.R. Nadel

Hugh Davson Distinguished Lectureship of the APS Cell & General Physiology Section
The Identification of the Sodium-Potassium Pump

Speaker: J.C. Skou

Horace Davenport Distinguished Lectureship of the APS Gastrointestinal Section
Speaker: I. Arias

The Bile Canaliculus: Biology and Pathobiology

Featured Topics

Point/Counterpoint: Is Active Muscle Mass an Important Target for Vasoconstriction during Exercise?
Moderator: C.M. Tipton

Point: In resting skeletal muscle, sympathetic activation produces vasoconstriction, which is thought to optimize blood flow to metabolically active muscles. However, the functional consequences of sympathetic activation in contracting skeletal muscle have been the subject of considerable debate. Previous studies in intact animals and humans have suggested that sympathetic vasoconstriction in contracting muscle is largely negated by metabolic vasodilation. This concept, initially termed "functional sympatholysis," recently has been extended by reductionist microcirculatory preparations demonstrating that certain local metabolic consequences of contraction interfere with specific signal transduction pathways mediating alpha-adrenergic vasoconstriction. Furthermore, the alpha adrenergic receptors, which are most susceptible to such metabolic inhibition, are those located on the distal nutrient arterioles, which are most accessible to the metabolic products of contraction, whereas adrenergic receptors located on more proximal resistance arteries are not so accessible to these metabolic products. By using both near infrared spectroscopy and Doppler velocimetry, we extend this concept by providing multiple new lines of evidence for functional sympatholysis in both rat hindlimb and human forearm muscle. Contraction-induced metabolic modulation of sympathetic vasoconstriction in mainly nutrient arterioles is a major protective mechanism that negates an otherwise deleterious effect of reflex sympathetic activation on skeletal muscle oxygenation.

Counterpoint: The increase in sympathetic vasoconstriction outflow to skeletal muscle, both active and inactive, during dynamic exercise is well established. The muscles vasoconstrict! In active muscles, this vasoconstriction depends on the intensity of sympathetic vasoconstriction and not on muscle etabolic rate—especially in those muscles whose composition is predominately one of red,oxidative fibers (muscle with white, glycolytic fibers may be an exception). The concept called `sympatholysis' (ametabolic inhibition of vasoconstriction) originated from the observed diminshing effects of sympathetic stimulation of the change (delta) in vascular resistance as muscle flood flow and metabolism both had risen. When re-plotting these effects as delta conductance (unaffected by flow), the results reveal the misleading effect of large changes inbaseline flow. The functional necessity of vasoconstriction in active muscles highlights the severe functional consequences that could attend sympatholysis were it a physiological phenomenon rather than a mathematical one.

Nongenomic Effects of the Gonadal Steroids on Vascular Function
Chairs: R.E. White and J. Stallone

Alterations in Redox State and Cell Signaling
Chair: D.G. Harrison

Gene Transfer to Blood Vessels
Chair and featured presenter: D.D. Heistad

Vascular Actions of Nitric Oxide Including Leukocyte-Endothelium Interactions, Vascular Permeability, and Angiogenesis
Chair and featured presenter: P. Vanhoutte

Cardiovascular Adaptations and Responses to Ischemia
Chair and featured presenter: J. Canty

Cardiac Electromechanics: The Development and Validation of Whole Heart Models
Chair and featured presenter: P. Hunter

Role of Membrane Traffic in Epithelial Transport Regulation
Chair and featured presenter: R. Frizzell

Chloride Channels: Mechanisms and Physiological Functions
Chairs: J. Hanrahan and D. Dawson

Understanding How Cells Sense Volume: New Sites and Insights
Chair and featured presenter: K. Strange

Signal Transduction in Somatosensory Pathways
Chair/featured presenter: W.D. Willis, Jr.

Raphe: Pain and Autonomic Integration
Chair/featured presenter: P. Mason

Molecular and Cellular Control of Insulin Secretion
Chair and featured presenter: F.M. Matschinsky

Insulin and Growth Factor Receptor Signaling
Chair: J. Avruch.

President-Elect's Symposium: Microcirculatory Studies of Inflammation and Immune Function
Chair: R.F. Tuma

Solomon A. Berson Distinguished Lectureship of the APS Endocrinology & Metabolism Section
Protein Metabolism and its Regulation by Hormones and Nutrients

Speaker: L.S. Jefferson

Carl W. Gottschalk Distinguished Lectureship of the APS Renal Section
Speaker: D. Brown

Modulation of Membrane Structure and Function in Transporting Epithelia: When Cell Biology Meets Physiology

Physiology in Perspective—The Walter B. Cannon Memorial Award Lecture
Speaker: A.E. Taylor

Starling's Hypothesis of Transcapillary Fluid Exchange: Then, Now, and the Future

Walter C. Randall Lecture in Biomedical Ethics
Speaker: F.Young

Biomedical Ethics in the 21^st Century: Human Cloning and Embryo Manipulation

Horace Davenport Distinguished Lectureship of the APS Gastrointestinal Section
The Bile Canaliculus: Biology and Pathobiology

Carl Ludwig Distinguished Lectureship of the APS Neural Control and Autonomic Regulation Section
Speaker: R.D. Foreman

Central and autonomic neural mechanisms of angina pectoris

Endothelial Factors in Cardiorenal Regulation
Chair: C. Wilcox

Neurohumoral Mechanisms in the Regulation of Blood Volume and Arterial Pressure
Chair: T. Lohmeier and J.T. Cunningham

Biodiversity Prospecting: The Use of Biological Adaptations in Industrial Applications
Chair: M. Heath

The Gravity of Circulation
Chairs: H.B. Lillywhite and A.R. Hargens

Glucose Uptake by Contracting Muscle
Chair: G.L. Dohm

Cell signals for glucose uptake: contractions dependent processes in skeletal muscle.

Interactions between the contraction-dependent and insulin-stimulated pathways in muscle.

Adventures in Liverland
Chair: I. Arias

The Bile Canaliculus: Biology and Pathobiology

The Neuroimmune Axis in Gut Inflammation: Clues to Therapy
Chair: J. Wallace

Second Messengers in Hypoxia
Chair: N.R. Prabhakar

Mitochondrial Maturation and Biogenesis in Striated Muscle
Chair: M.A. Portman

Maturation of mitochondrial respiration in heart in vivo

Vagal Mechanisms in Neural Control
Chairs: D. Mendelowitz and A. Travagli

Brainstem vago-vagal reflex control of the gut

Neuroendocrinology

Regulation of Sympathetic Function by Nitric Oxide
Chair: J. Zanzinger

Modulation of sympathetic excitability by nitric oxide

Genetic Models and Novel Tools: Application of Physiological Genomics to the Study of Neural Control of Cardiovascular Function
Chair: R. Davisson

Insights into the role of the brain renin-angiotensin system in cardiovascular regulation through targeted manipulation of the mouse genome

Membrane Trafficking and the Regulation of Ion Transport Proteins
Chairs: M. Caplan and J. Lippincott-Schwartz

Sorting of ion transport proteins: molecular signals and physiologic regulation

Real time analysis of secretory membrane traffic

Control of Renal Function by Cytochrome P450 Eicosanoids
Chairs: R.J. Roman and J. Imig

P450 metabolites of arachidonic acid: novel second messengers regulating renal tubular and vascular function

Mechanisms and Regulation of Epithelial Calcium Transport: Genetics Illuminating Physiology
Chair: P. Friedman

The ins and outs of transcellular calcium absorption

Calcium-sensing receptor: A versatile mediator of the diverse actions of extracellular calcium on cellular function

Remote Monitoring of Physiological Functions
Chairs: D. Jones and P. Butler

Physiological and Molecular Responses of Peripheral Chemoreceptors to Chronic Stimuli
Chair: G.E. Bisgard

Signal transduction and gene regulation by hypoxia

Mechanisms of Lung Alveolar Epithelial Injury
Chairs: S. Matalon and M.A. Matthay

Modulation of ion transport across epithelial cell by reactive oxygen nitrogen intermediates

Intact alveolar epithelial fluid transport: An excellent predictor of morbidity and mortality in clinical acute lung injury

The Medullary Raphe: Such an Obvious Role in Respiratory Control, but What Exactly is It?
Chair: G. Richerson

Insights into the role of the medullary raphe in respiratory control from neurochemical cytoarchitecture

Raphe neuronal assemblies in calm and crisis

Mechanisms of Lung Vascular Development
Chair: J.M. Shannon

Transcription factors in vascular development: homeobox gene XHex

Cytokines and Body Temperature in Health and Disease
Chair: C. Blatteis

Cytokines and body temperature in health and disease

Regulatory Peptides, Guanylin, Uroguanylin and Lymphoguanylin and their Cognate Receptors
Chair: L.R. Forte

Regulation of the Epithelial Na Channel
Chair: M.S. Awayda

Osmolality and related messengers of apical sodium channels

Neural Circuitry of Body Fluid and Cardiovascular Homeostasis
Ernest H. Starling Distinguished Lectureship of the APS Water and Electrolyte Homeostasis Section
Parallel and Complementary Neural Mechanisms in the Maintenance of Body Fluid and Cardiovascular Homeostasis

Speaker: K. Johnson

Featured Topics/Poster Discussions

Muscle Fatigue
Chair: T.M. Nosek

Use of Transgenic and Knockout Models for the Study of GI Function
Chair: M. Donowitz

Teaching and Educational Innovation
Chair: J. Griswold

Poster discussions

Blood Volume Regulation
Chair: E.R. Nadel

Graduate Student Posters in Respiration Physiology

Workshops

Teaching Critical Thinking Skills in Physiology: An Interactive Workshop
Chairs: S. Mierson and A.P. McNeal

"How can I get my students to think?" is a question asked by many faculty. Research shows that lectures organized to convey large amounts of information are not necessarily the best way to teach critical thinking skills. This workshop will demonstrate recent teaching methods designed to foster such skills, which include organizing information, not just ingesting it; identifying what you do not know and asking questions to address specific areas of need; being able to ask, What is the evidence?; critically examining evidence; generating ideas and hypotheses about physiological questions; applying previously learned concepts to new situations, and designing experiments to test hypotheses. Each presenter will describe a method and lead an activity, allowing participants experience the method as the students would in a classroom.

Demonstrated methods will include small-group problem-based learning, which helps students think critically and develop habits of life-long learning; close reading of published research papers in order to teach basic physiological concepts and analytical skills for evaluation of data and experimental design; teaching physiology to a large (200) class of first-year medical students based on the concept that group or team learning facilitates learning by the individual; examples of `framework' experiments in which the techniques and overall design are given within which students can design their own experiments quite freely. Participants will then work on a structured exercise for revising their own experimental labs.

Physiologists and Outreach Activities Directed to Lower Primary Grades
Chairs: J. Schadt and B.E. Goodman

For many of us, our lifelong interest in love of science began in the lower primary grades. In the interest of continuing this capture of young minds, this workshop intends to encourage and facilitate APS member outreach activities directed at lower primary grades (i.e. K-5). The workshop will consist of four short talks and active participation in several hands-on, inquiry-based activities appropriate for grades K-5. Discussion will include the importance of outreach, from a physiologist's perspective and from the standpoint of a public school teacher, and how to get started. Examples of hands-on, inquiry-based activities for grades K-5 will be presented. All activities will be appropriate for grades K-5, inexpensive to set up, and easy to do. Sheets of instructions and lists of materials required for each activity will be provided.

Refresher Course

Teaching Cardiovascular Physiology
Chair: F.L. Belloni

This course reviews concepts and teaching strategies related to cardiovascular physiology, which is a major component of mammalian physiology courses in undergraduate colleges, in graduate programs, and in the professional school curricula for medicine, dentistry, and allied health professions. In many cases, these course sections are assigned to teachers whose own professional expertise is in another area of physiology or in a subspecialty within cardiovascular physiology. This course is to provide these teachers with a succinct summary of current concepts in cardiovascular physiology, including recently developed concepts that are appropriate for introductory physiology courses in undergraduate, graduate, and professional curricula. In addition, the course will offer guidelines and suggestions about teaching strategies and instructional resources related to cardiovascular physiology. The didactic component of the session will consist of three lectures by noted experts in cardiovascular physiology, who are also excellent teachers. Each lecture will deal with a subfield of the overall topic—cardiac muscle, vascular physiology, and integration and regulation—and will be followed by a question-and-discussion period. There will also be a general discussion and question session at the conclusion of the lecture component and poster presentations (from abstracts submitted to the refresher course topic category), demonstrations (e.g., computer simulations, audiovisual teaching material), and exhibits (e.g., textbooks, course syllabi, problem-based learning cases).

American Society for Pharmacology and Experimental Therapeutics

Symposia
Cytochrome P450 and Chemical Toxicity in the Respiratory Tract
Chair: J.R. Bend

There is much interest in the role of the cytochrome P450 monooxygenase system in the respiratory tract, regarding its ability to modulate cell selective toxicity via the metabolic activation of xenobiotics and endobiotics and the ability of pathobiological stimuli to regulate this system in an isozyme specific manner. This symposium will bring together experienced scientists who have made seminal contributions to this research area over the last decade.

Use of Mutant Mice as Models for Cardiovascular Disease
Chair: D.J. Lefer

Gene knockouts and transgenics are timely and leading topics in cardiovascular research. Participants will discuss ecNOS gene deletion mice in myocardial ischemia/reperfusion; iNOS gene deletions in endotoxic shock; Cu/Zn SOD trangenic mice in hepatic and intestinal ischemia/reperfusion, and genetic mutation of myocardial beta-adrenergic receptors and receptor kinases.

Signal Transduction and mRNA Turnover
Chair: D.R. Schoenberg

Developments in many different fields have increasingly shown alterations in mRNA turnover as a key element in gene expression. This symposium will address the evolving relationship between signal transduction and mRNA turnover.

The Molecular Basis of Cytokine Action in Neuronal Injury and Disease
Chair: A. Symes

Cytokines harness specific signal transduction pathways and transcription factors. While many of these pathways have been described in other cell types, application of this to the nervous system is often much slower in being described. This symposium will examine four different cytokines and describe the mechanisms of their action in neural tissue and the relevance of these cytokines to the etiology or treatment of specific diseases.

Modulation of Cell Signaling by 14–3-3 Proteins
Chair: H. Fu

Recently, biologists studying a wide range of processes have encountered the same family of proteins, termed 14–3-3. 14–3-3 is found to bind diverse protein ligands that include receptors, signaling mediators and adaptors, and virulence factors. This symposium will look at this rapidly expanding field to discuss the molecular paradigms which can account for the diverse roles of 14–3-3 and the tremendous impact on many other fields in pharmacology that have just begun to touch 14–3-3 proteins.

Estrogen Metabolism and Carcinogenicity
Chairs: T.J. Monks and J.L. Bolton

This symposium will bring together several investigators who have been focusing their research efforts on the mechanistic role of estrogen metabolism in estrogen-mediated carcinogenesis. Particpants will address an important evolving concept in connection with the mechanism of action of steroids: the extent to which steroid hormones may modulate cellular functions through mechanisms other than the classical steroid receptors.

Central and Peripheral Glutamate Receptors: Role in Cell Toxicity and Tissue Injury
Chair: S.I. Said

This symposium will highlight recent developments in glutamate receptor research, with special reference to the role of activation of these receptors in cell death, both in the brain and in peripheral tissues. The symposium should stimulate investigation into the potential significance of these receptors as mediators of tissue injury, and as targets for drug action.

Vascular 5-HT Receptors: Pharmacology and Pathophysiology
Chairs: S.W. Watts and M.L. Cohen

Speakers will update the current standing/nomenclature and pharmacology of 5-HT receptors and will focus on receptors newly implicated in modulation of vascular function and/or implications for these receptors in disease.

Flavin-Containing Monooxygenases: Molecular Aspects of Variability in Humans
Chair: M.P. Lawton

In recent years, it has become apparent that a gene family represents the mammalian flavin-containing monooxygenase, an enzyme that catalyzes the oxygenation of numerous heteroatom-containing molecules, with five members. Expression of these genes is regulated in a tissue, species, and sex-dependent manner. Speakers will review recent advances in our understanding of FMO structure/function and gene expression.

G-Protein Coupled Receptor Kinase (GRK) Function and Regulation: Implications in Human Disease
Chair: R.J. Lefkowitz

This symposium will focus on the advances in our understanding of the important role of GRK regulation as a mechanism for alterations in receptor/G-protein coupling. Topics include GRK regulation in heart failure and hypertension and the role of GRKs in GPCR signaling.

Molecular Mechanisms of Chemical Teratogenesis
Chair: P.G. Wells

Almost 50 years after the thalidomide tragedy, it is only recently that a variety of biochemical and molecular biological approaches begun to reveal the mechanisms by which drugs and environmental chemicals can cause structural and functional birth defects. A comprehensive view of four major approaches toward explaining the mechanisms of chemical teratogenesis and determinants of susceptibility will be provided.

Molecular Structure, Function and Pharmacology of Neuronal Nicotinic Acetylcholine Receptors
Chair: T. Narahashi

Once the molecular structure of the neuronal ACh receptor was determined, the door was opened for contemporary pharmacology to study neuronal nicotinic AChR by using a variety of advanced technologies. This development has been facilitated and catalyzed by various discoveries including, but not limited to 1) the role of the brain cholinergic system in Alzheimer's disease and 2) renewed interest in the action of nicotine as the harmful effects of tobacco have become a serious social and medical issue. These two complementary symposia will address an area that has created explosive scientific interest in the past few years.

Protein Kinase Complexes
Chair: M.H. Cobb

Participants will look at the importance of protein-protein interactions, which are critical in the regulation of enzymes and receptors controlling metabolism and membrane signaling events. It is now appreciated that protein-protein interactions are essential for the appropriate control and targeting of not only tyrosine but also serine/threonine protein kinase cascades.

Recent Advances in Molecular Mechanisms and Pharmacological Interventions of Lung Fibrosis
Chairs: S.N. Giri and S.H. Phan

The expert panel will present an integrated picture of the molecular basis of pathogenesis of lung fibrosis and its management by novel pharmacological approaches.

Bradykinin: Recent Developments Regarding Structure, Metabolism, and Receptor Regulation
Chairs: R.A. Skidgel and M.P. Merker

Experts in different areas of bradykinin research will discuss some of the most recent discoveries in this area and demonstrate how current technologies are being used to explore the function of a peptide that has garnered such longstanding and widespread attention. This information will further better understanding of the uses of this peptide as a research tool and advances in the therapeutics of the cardiovascular system and of inflammation.

Function and Pharmacology of the Vesicular Neurotransmitter Transporters
Chair: L.E. Eiden

A growing field for pharmacologists, physiologists, and anatomists is how a new molecular understanding of vesicular transporters is being applied to the study of the basic mechanisms of neurotransmission, and the etiology and pathogenesis of human diseases of chemical neurotransmission. The speakers have made seminal contributions to this field that spans molecular biology, genetics, and chemical neuoranatomy, based on studies in isolated synaptic vesicles, nematodes, rodents, and human subjects.

Regulation of the Adenylyl Cyclases
Chair: H.K. Hammond

Much of the initial focus of labs studying regulatory mechanisms in Gs-linked adenylyl cyclase paths has been on receptor/G-protein regulation. The importance of regulation at the level of the enzyme has only more recently been appreciated, and advances in this area will be highlighted at this symposium.

New Targets for Antiparasitic Chemotherapy: Metabolic Enzymes, Channels and Transporters
Chair: M.A. Phillips

This symposium will focus on mechanisms of drug action and drug resistance, as well as the identification of new drug targets in parasitic pathogens. A broad range of biological systems is covered, from metabolic enzymes to channels and transporters.

Herbal Medicine: Pharmacology and Research
Chair: C.N. Gillis

Speakers will focus on selected research on plants and photomedicinals, the interactions of such products with prescription medications and proposals for future study in this field. The primary goal of the symposium is to encourage interest in scientifically sound studies of medicinal plants among basic and clinical scientists.

Angiotensin in Normal and Abnormal Growth of Cardiovascular Tissue
Chairs: K.H. Berecek and R. Levi

This symposium will focus on new developments in Angiotensin Il receptors, pharmacology of new RAS agents, pathophysiology of All in myocardial ischemia, cardiac hypertrophy and failure, and on the clinical pharmacology of AT1antagonists and ACE inhibitors.

RGS GTPase-activating Proteins in G-Protein Signaling
Chairs: P.C. Sternweis and E.M. Ross

This symposium will explore the multiple and still unfolding roles of RGS proteins (Regulators of G protein Signaling) in signal transduction. These proteins are GTPase activating proteins (GAPs), but may serve many functions in addition to simply attenuating signaling.

Lysophospholipid Signaling in Mammals: New Insights from Cloned Receptors
Chair: J.M. Chun

Symposium speakers will examine what is known about lyso-phospholipid signaling, focusing on what has been gained from the expression and characterization of the receptor, explore downstream signaling events, and assess biological function. The lyso-phospholipid signaling pathway offers the possibility of developing new therapeutic targets in altering the normal and diseased states.

Adenosine Receptors in Heart and Brain
Chair: T.V. Dunwiddie

An examination of the physiological role(s) played by adenosine in heart and brain will compare and contrast the physiological, cellular, and molecular consequences of adenosine receptor activation in these two tissues. Understanding the basic functional role played by adenosine in heart and brain may help to provide insights into the development of therapeutic drugs that can interact with adenosine receptors.

Molecular Control of Sodium Channel Density and Localization in Neurons
Chair: L.L. Isom

The speakers' objective is to present and discuss a central question in sodium channel biology: what are the key determinants of sodium channel localization and clustering? Are these events orchestrated by the oligodendrocytes, by the cytoskeleton, or by the sodium channel subunits themselves acting as a bridge of communication between the extracellular matrix and intracellular proteins?

The Role of Renal Dopamine Receptors in Hypertension
Chair: P.A. Jose

The role of peripheral dopamine in the regulation of renal function is beginning to be understood. Recent studies have shown that an abnormality in either the renal production and/or action of dopamine may be responsible for the development and maintenance of genetic or other forms of hypertension. This symposium will be an ideal forum from which experts in the field will provide the most up-to-date information in this exciting and important new area of research.

Mitochondrial Dysfunction and Neurodegeneration
Chair: P.K. Sonsalla

Speakers will provide an overview of mitochondrial function and neuronal dysfunction and cell death. There is considerable effort exerted by pharmaceutical companies as well as academicians to find effective and efficient treatment for neurodegeneration, both as prophylaxis and as replacement therapy after onset of the loss of neurons.

Colloquium

Neurotoxicity of Amphetamines and Related Stimulants

Chairs: D. Kuhn and G. Hanson

Abuse of amphetamine drugs and the added hazard of neurotoxicity is the subject of this colloquium. A number of exciting and novel results are emerging from this field, including preclinical studies that could lead the way to the development of preventive and therapeutic strategies. The selectivity of the neurotoxic effects of the amphetamines is remarkable, and studies of their mechanisms of action are likely to have wide applicability to other forms of neurotoxicity and neurodegeneration.

Short Course

Surfing the Genome

Chair: D. Port

Speakers will discuss the use of genechip probe arrays for gene expression profiling and genotyping of single nucleotide polymorphisms; closing the gap between sequence and function–the frontier of computational biology and functional genomics; cDNA expression arrays–now and beyond; bioinformatics and G-protein-coupled receptors, and gene expression products–micro and macro arrays, software, and service.

Workshop

A Call to Activism
An almost 15% increase in the FY'99 NIH budget was the first step of a 5-year plan to double the agency's budget within that time. Congressional support is strong, but scientists must make a compelling case to lawmakers for continued federal investment in NIH. This workshop will provide an overview on what part you can play to help insure NIH receives continued strong congressional support. Learn the dos and don'ts of making effective presentations to your Members of Congress. Learn how to win support and shape the debate in Washington and back home.

Burroughs Wellcome Fund Lecture

Speaker: Jean-Pierre Changeux

The Nicotinic Acetylcholine Receptor and Synaptic Plasticity

1999 ASPET Teaching Institute

Pharmacologists of the Future: Who Are They and Where Will We Find Them?
Chairs: R. Schwartz-Bloom and R. Long

The competition for a pool of outstanding students choosing to pursue graduate study in pharmacology is keen. This workshop will be devoted to discussing issues relevant to recruitment and training in pharmacology. Workshop panelists will address specific topics in recruitment and training, highlight areas that are working well, and discuss unsolved problems. Pharmacology faculty and chairs, directors of PSTP, and MSTPs are encouraged to attend. Attendees will be asked to join in the discussion.

Graduate Student Convocation and Reception

Career Opportunities for Pharmacologists in Government
Chair: G.M. Stancel

Speakers at this year's Graduate Student Convocation will discuss career opportunities for pharmacologists and other biological scientists in major government agencies, including the Environmental Protection Agency, The Food and Drug Administration, the Centers for Disease Control, and the U.S. Department of Agriculture. All attendees are invited to a reception immediately after the convocation to talk individually with the speakers and other senior members of ASPET.

American Society for Investigative Pathology

Symposia
Extracellular Matrix and Signaling
Chairs: R.V. Iozzo and K.K.H. Svoboda

Extracellular matrix exerts profound effects on tissue homeostasis and regulates the ability of cells to migrate, proliferate, and generate an angiogenic response. This symposium encompasses three major themes that are fundamental to both development and tumorigenesis. The topics, which will interest anatomists, cell biologists, and pathologists, will include the role of angiopoietins in the initiation of normal and pathological neovascularization; the central role of extracellular matrix and integrins in the control of cell proliferation, apoptosis, and cancer, and key molecular interactions that play a role in the pathogenesis of atherosclerosis. Participants will also address important biological questions related to novel aspects of extracellular matrix and to the molecular mechanisms regulating how cells respond to changes in the outside environment.

Molecular Basis of Wound Healing
Chairs: W.C. Parks and W.A. Muller

Wound healing involves an orderly progression of events that re-establish the integrity of the damaged tissue. The initial injury starts a programmed series of interdependent yet separate responses, including re-epithelialization, inflammation, angiogenesis, and matrix accumulation, among others. Speakers will address how specific molecules, such as matrix components, cytokines, proteinases, and receptors, interact and function in order to control cell behavior during healing.

Molecular Models of Parasite-Tissue Interactions
Chair: J.H. McKerrow

The host-parasite relationship represents one of the most evolved and complex interactions in biology. This symposium will highlight recent developments that have helped us understand the molecular cross-talk between parasites and host cells or tissues. Topics include how multicellular parasite larvae invade skin; the pathogenesis of amoebic colitis; the complex cytokine pathways involved in granuloma formation, and the elegant interaction between malaria-infected red cells and vascular endothelium.

Host Defense Mechanisms
Chairs: V. Kumar and C. Biron

This symposium will focus on innate host defense mechanisms, including those mediated by natural killer cells, neutrophils and mast cells and cytokines that regulate these cells. Participants will also explore the interactions between the innate and adaptive host defenses systems. The discussion will include both cellular and tissue changes.

Trends in Experimental Pathology: Molecular Profiling
Chair: E.R. Unger

Molecular profiling is a rapidly expanding field that includes a variety of novel techniques to achieve high throughput sequence analysis as well as analysis of gene expression. These techniques present unique opportunities and challenges for implementation in studies of disease pathogenesis and diagnosis. Speakers will delineate the current and potential applications of molecular profiling techniques to pathology, discuss approaches to managing and understanding the vast data that results from these techniques, and describe problems that need to be addressed before we can envision widespread applications of these techniques.

Vascular Complications of Diabetes
Chair: D. Stern

The vascular complications of diabetes are particularly devastating, as they affect virtually every organ. This session addresses mechanisms underlying diabetic vascular complications focusing on the role of nonenzymatic glycoxidation and the lipoxygenase pathway. Formation of advanced glycation endproducts (AGEs) by glycoxidation alters functional and structural properties of the parent macromolecule. Increased levels of glucose and oxidant stress, both characteristic of the diabetic microenvironment, accelerate AGE formation. Deposition of AGEs has been associated with vascular complications in diabetes. Discussion will center on intracellular glycoxidation and its effect on cellular expression of growth factors and other important cellular mediators; studies of the receptor for AGEs (RAGE), including its role as a signal transduction receptor for AGE-mediated perturbation of cellular behavior contributing to diabetic macrovascular disease and impaired wound healing, and the role of 12-lipoxygenase in vascular and inflammatory cell dysfunction, and its implications for vascular biology and diabetes.

American Society for Nutritional Sciences

Symposia
Bioactivity in Human Milk and Bacterial Interactions in the Developing Immature Intestine
Chairs: R. Schanler and L. Duffy

The developmental regulation and nutritional processes that influence toxin interaction within the developing intestine are important to the understanding of bacterial infection in premature infants. By understanding the biological significance of bacterial interactions and effector responses to nutrients and bioactive substances in human milk, new approaches may be available in the prevention and treatment of gastrointestinal disease, principally necrotizing enterocolitis, in the premature neonate. Participants will review and highlight the role of human milk and the developmental influences on bacterial toxin expression in intestinal responsiveness to specific bacterial interactions in gut maturation and mucosal immunity in the immature intestine.

Diet, Natural Products and Cancer Chemoprevention: Progress and Promise
Chairs: K. Singletary and S. Lippman

It is widely recognized that cancer is a preventable disease; in particular, it has been estimated that one-third of cancer is associated with poor nutrition and diet. This symposium will focus on the progress made in identifying dietary factors and natural products that have demonstrated effectiveness in preventing cancer or have considerable potential for use as chemical agents in cancer-preventing strategies (chemoprevention). This session will provide an insightful and stimulating update on promising developments in this rapidly emerging area of cancer research, with the goal of encouraging new and creative research initiatives in cancer prevention.

Dietary Zinc and Iron–Recent Perspectives Regarding Growth and Cognitive Development
Chairs: H.H. Sandstead and P. Lofgren

This symposium will update recent perspectives on the important role of dietary zinc and iron in growth and cognitive development. The speakers will present diverse perspectives—from work in developing countries on nutrition and behavior, to views of a behavioral research psychologist on methodology issues, to studies with primates, and clinical perspectives from studies with infants and young women.

Diet and Obesity: Do We Need to Look Beyond Fat?
Chairs: S.B. Roberts and M.B. Heyman

Research over the past decade has focused heavily on the role of high dietary fat in the development of obesity. Currently, there is a general perception that high levels of dietary fat promote hyperphagia and lead to weight gain. Recent research, however, suggests that other dietary variables such as energy density, the glycemic index, fiber, meal patterning, and dietary variety and palatability may be more important. The distinction between fat and these other dietary variables is particularly important because, although they are usually closely associated, this result is not inevitable. Increasingly, commercial products separate fat from the other dietary variables usually linked to fat, and consumption of these products may promote obesity rather than the reverse if indeed fat is not a primary cause of hyperphagia.

Participants will discuss the latest research on the relative influence of different dietary factors on hyperphagia and body fatness. We anticipate that this information will be of real importance to the nutritional and medical communities, because it will encourage a unified approach to the dietary prevention and management of obesity.

Energy Expenditure and Obesity: Critical Factors and Critical Stages
Chairs: J. Cunningham and M. Goran

This symposium reviews the impact on energy balance and obesity that occurs at critical stages of the lifespan or as a result of major physiologic alterations. In- depth treatments of metabolic, endocrine, genetic and environmental influences will be provided. Although the emphasis is on obesity in humans, topics include lessons from animal studies as well as knowledge gained from a transgenic mouse model.

Homocysteine, Aging, and Geriatric Diseases
Chairs: C.L. Krumdieck, C.W. Prince, and J. Selhub

Under normal conditions, the concentration of total homocysteine (tHcy) in plasma does not exceed 15 umoles/L. Higher levels define hyperhomocysteinemia and are associated with many serious clinical manifestations. If severe, as in the rare inborn error of metabolism homocystinuria (tHcy100 umoles/L), often lethal thromboembolic vascular occlusions of arteries and veins, arteriosclerosis without lipid deposition, osteoporosis, thrombofilia, and ectopia lentis are found before age 20y. A large body of epidemiological evidence has now demonstrated that low-grade hyperhomocysteinemia (tHcy 16 to 50 umoles/L), a common condition, is a major independent risk factor for numerous diseases characteristic of old age, primarily, arteriosclerosis, occlusive vascular disease of arteries (coronary, cerebral and peripheral) and veins, and possibly osteoporosis and cognitive decline, which together account for much of the morbidity and mortality in the aged. Although no single mechanism has been proposed to explain the multi-system toxicity of hyperhomocysteinemia, it seems clear that long-term exposure to moderately elevated levels can produce similar manifestations to those observed after shorter exposures to higher levels. The possibility that Hcy, a highly reactive thiol, or its thiolactone, an `activated' cyclic thio-ester, react spontaneously in a time- and concentration-dependent manner with cysteinyl and lysyl residues of long-lived extracellular proteins (e.g., fibrillin I) with consequent loss of their biological functions, has been proposed as a key determinant of its toxicity. Protein homocysteinylation can be envisioned as similar to protein glycation, the reaction of proteins with glucose in protracted hyperglycemia, believed to cause many of the complications of diabetes. Damage to endothelial cells with abnormal release and/or function of nitric oxide (the endothelium-derived relaxing factor, EDRF), a stimulatory effect of homocysteine on the proliferation of vascular smooth-muscle cells, inhibition of growth and hypomethylation of cell-cycle regulators in vascular endothelial cells, and possible oxidative damage resulting from the homocysteine-mediated generation of free radicals are being investigated as putative mechanisms of Hcy toxicity. All may be involved.

Hyperhomocysteinemia may be envisioned as a determinant of aging; its impact could be lessened by appropriate nutritional interventions known to lower tHcy levels (e.g., supplemental folic acid and vitamin B6, and restriction of methionine). Participants will examine the evidence currently available in support of these hypotheses.

Improving Adolescent Iron Status before Childbearing
Chairs: K. Kurz and R. Galloway

Is improving iron status before a woman's first pregnancy a feasible approach for improving women's iron status in general, and birth outcomes in particular? This idea has received limited rhetorical and programmatic support, but has hardly been addressed by the scientific community. Participants will explore the possibility that one way to improve iron status during pregnancy is to improve it before the first one occurs, which suggests a new focus on adolescent girls. In this symposium, the scientific benefits of treating anemia and improving iron status before pregnancy will be examined, and the operational issues of adding this target group to others usually considered for anemia control programs will be addressed in studies from Indonesia, India, and Peru.

Mechanistic Aspects of Vitamin and Coenzyme Utilization and Function
Chairs: A.H. Merrill, B. Bowman, and P.C. Preusch

The symposium recognizes the distinguished career of Professor Donald B. McCormick by highlighting various mechanistic aspects of water- and fat-soluble vitamin absorption, transport, metabolism and biological function. Discussions will center on vitamins and cancer; biotin utilization by proliferating human lymphocytes; possible roles of lipases and carboxylesterases in the hepatic utilization of vitamin A; studies of the mechanisms of biological intermolecular transfer of reduced flavin; structure-function studies of mammalian methylenetetrahydrofolate dehydrogenase-cyclohydrolases, and interrelationships between vitamin B6 and the metabolism of essential fatty acids and vitamin B6.

Physical Activity and Breast Cancer Risk
Chairs: C.A. Swanson and R. Ballard-Barbash

A sedentary lifestyle is associated with increased risk of developing a variety of chronic diseases. This symposium will examine the relation of physical activity and breast cancer risk. While not definitive, epidemiologic data suggest that physically active women are at lower risk of breast cancer compared with sedentary women; the magnitude of risk reduction has not been established. It appears that physical activity rather than physical fitness is the relevant exposure. The relevant exposure period(s) has not been defined. A variety of instruments to assess physical activity have been used in epidemiologic studies. The variable quality of instruments may have contributed to inconsistent findings in the epidemiologic literature; few instruments have been validated. A biological explanation for a protective effect of physical activity has not been determined. Since it is widely thought that breast cancer is mediated through exposure to estrogen, attention has focused on reproductive factors and estrogen metabolism. The effect of physical activity may be mediated through energy balance and changes in body weight. Experts in epidemiology, exercise physiology, and endocrinology will discuss these issues.

Probiotic Bacteria: Implications in Human Health
Chairs: D. DiRienzo, T. Klaenhammer, and W.N. Reynolds

A rational approach for studying probiotic bacteria is necessary for establishing their health usefulness to humans. This symposium brings together several leading researchers in the field of probiotics. Critical issues include an understanding of clinical or health maintenance effects, what strains and what levels are needed to achieve the effects, mechanisms for the effects, and microbiological characteristics of the strains needed to maximize the effects. The program focus will serve to update attendees on the state of clinical and mechanistic research in this field, the future potential for probiotic bacteria to play a useful role as a health-enhancing ingredient in our food supply, and priorities and considerations for future research.

The Regulation of Muscle Mass
Chairs: K.S. Nair and P.J. Reeds

This sym