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Experimental Biology 2003

Translating the Genome

April 11–15

San Diego, CA

	INTRODUCTION

TOP INTRODUCTION The American Physiological... American Society for... American Society for... American Society for... Nutritional Sciences American Association of...

 
This year’s meeting of professional research scientists is being developed, sponsored, and coordinated by six FASEB societies—The American Physiological Society, American Society for Biochemistry and Molecular Biology, American Society for Pharmacology and Experimental Therapeutics, American Society for Investigative Pathology, American Society for Nutritional Sciences, and American Association of Anatomists—and by various guest societies. A sampling of the multidisciplinary sessions, listed by host societies, appears below. The abstract issues of The FASEB Journal and the meeting program contain full details and are mailed to preregistrants before the meeting. For up-to-date information, visit http://www.faseb.org.

	The American Physiological Society

TOP INTRODUCTION The American Physiological... American Society for... American Society for... American Society for... Nutritional Sciences American Association of...

 
Symposia
Lineage Specific Programming of Stem Cells into Tissues
Chair: Q. Al-Aqwati

The goal of this symposium is to provide an update on stem cell biology and the genetic program that underlies the distinctive physiologic functions of differentiated tissues. All specialized tissues including kidney, brain, heart, endothelium and blood originate from a single cell. The generation of tissue diversity depends upon coordinated sequential genetic programming of the progeny of this cell resulting in the differentiated phenotype in specific tissues. Following organogenesis, each tissue is not only able to replenish its constituent cells over the lifetime of the organism, but also to regenerate in response to injury. These processes depend upon the persistence of a small reservoir of stem cells capable of providing an endless supply of differentiating cells to repopulate the each organ. The participants of this symposium will overview recent insights into the mechanisms by which cells acquire tissue specific programs. Dr. Ron McKay will overview stem cells and the signals that result in their neuronal differentiation, focusing on refined approaches to physiological characterization of their neuronal lineage for treatment of Parkinson’s disease. Catherine Verfaillie’s group (University of Minnesota) has identified a unique antigenically marked human marrow derived progenitor cell that differentiates into endothelium and contributes to angiogenesis in vivo. Leonard Zon (HHMI/Harvard) will discuss the genetic programming of hematopoietic progenitor cells to form red blood cells. Using ENU mutagenesis his group has defined 26 unique genes required for hematopoiesis. Several of these genes are also required for normal vasculogenesis, CNS function and renal development of the kidney. Finally Dr. Qais Al-Awqati (Columbia University) will discuss evidence for stem cell niches in the kidney and the antigenic and functional features that define these hitherto elusive cells. Through this discussion, the audience will be apprised of the interface between stem cell biology and organ physiology.

Career Planning for Experimental Biology, Biomedical and Physician Scientists
Chair: K. L. Barker

Career opportunities for experimental biologists, biomedical scientists and physician-scientists have changed over the past few years. Driving these changes are: 1) the rapid private sector application of new experimental biology discoveries conceived in university laboratories to diagnose and treat human, other animal and plant diseases, and to generate new products, 2) the unprecedented growth in research funding from both public and private sources, 3) the increased dependency by universities on soft money sources such as research grants, clinical income and intellectual property for support of faculty, 4) the expanded complexity of experimental biology research that now requires very expensive, rapidly changing technologies and equipment, and a collaborative research-team approach to accomplish, and 5) the growing importance of translational investigators, particularly physician-scientists, who can facilitate the rapid application of new fundamental findings toward new clinical applications. These forces mean that a growing proportion of newly trained experimental and biomedical scientists will be employed by industry instead of by universities, there will be an increased demand on the time of those who take academic positions to generate their own salary support from research grants and clinical income, there will be a loss of job security that can provide meaningful bridge support between grants in times of economic down-turn, there will be a loss of opportunity to function and be recognized as an independent investigator, and there will be a general reduction in the reciprocal commitment and loyalty between the scientist and his or her employer. Scientists-in-training must be aware of the reality of these trends and prepare for both the complications and special opportunities these issues will present during their career. This symposium will present the career planning perspectives and recommendations of a university administrator (medical school dean), an industry person responsible for hiring biological and biomedical scientists for his/her company (personnel director), a granting agency program administrator who is knowledgeable about the training of physician-scientists (NIH-MSTP program officer), and a biomedical scientist who is making his/her way in this complicated new academic/research/clinical environment.

Modulation of Respiratory Motoneurons from Molecules to Behavior
Chair: A. J. Berger

Modulation of respiratory motoneurons by endogenous and exogenous substances can profoundly alter motoneuron behavior. In recent years state-dependent modulation of hypoglossal motoneurons (HMs) is thought to be a key factor in obstructive sleep apnea (OSA). The relative contribution to the sleep-state-dependent reduction in HM excitability by two mechanisms, one disfacilitation (withdrawal of serotonergic and adrenergic facilitatory inputs) and the other enhanced active inhibition (primarily glycinergic) is controversial. The four speakers will present their results exploring how these two mechanisms can lead to a reduction in HM excitability. First, Leszek Kubin will discuss the co-expression of mRNA for distinct serotonergic and adrenergic receptors and the developmental changes that occur in selected mRNAs and the corresponding receptor proteins in HMs. Second, Douglas Bayliss will discuss cellular and ionic mechanisms by which motoneuronal excitability is regulated by H⁺, neurochemicals (such as 5-HT and norepinephrine) and inhalational anesthetics. He will show that leak K⁺ channels, with properties of the two-pore-domain, pH-sensitive TASK channels, represent ion channel targets common to these chemically diverse modulators. Differential modulation of TASK channels provides a mechanism for dynamic regulation of motoneuronal excitability. Third, Albert Berger will discuss the importance of enhanced glycinergic inhibitory synaptic transmission to HMs during rapid eye movement sleep. He will show how 5-HT can reduce such inhibitory activity. He will discuss recent studies showing that ethanol, which is known to exacerbate OSA, can enhance glycinergic inhibitory synaptic transmission. Further the mechanism of ethanol action on glycine receptor properties will be presented. Finally, Richard Horner will describe his experiments of modulation of neurotransmission in freely behaving rats and show the differential effects of 5-HT in modulating hypoglossal motor outflow and reflex responses across natural sleep-wake states. He will also describe the role of endogenous glycine and GABA in modulating hypoglossal motor outflow and reflex responses across natural sleep-wake states.

Epithelial-Neuronal Interactions Underlying Bladder Gene-Regulation and Sensory Function
Chair: L. A. Birder

Recent studies support the idea that urothelial cells exhibit specialized sensory and signaling properties that allow them to respond to their environment and communicate with neighboring bladder nerves. These properties include the release of mediators (nitric oxide, NO; ATP) and expression of receptors such as the capsaicin receptor, VR1 as well as a subfamily of VR1 related molecules. Complementary presentations will detail the nerve urothelium communication that relays normal and pathological signals from the bladder. For example, data from targeted P2X1, P2X2 and P2X3 gene-deletion studies in mice confirm a significant role for purinergic transmission in afferent as well as efferent control of urinary reflexes. Activation of P2X3 and/or P2X2 receptors represents a critical step in relaying bladder-filling information to the CNS. In addition, the properties of bladder urothelium and afferents are plastic and can be changed by pathology. Characterization of gene expression profiles has identified a number of genes, which are up regulated in the bladder following inflammation (eg., iNOS, NGF, NFB and protease activated receptor, [PAR]). Cross talk between genes such as PAR and ion channels can influence afferent excitability and possibly epithelial function. Thus, elucidation of neural-epithelial signaling mechanisms may provide insights into the pathology of visceral dysfunction.

Mitochondrial Regulation of Cell Function
Chair: J. Bhattacharya

Although mitochondria are best known as suppliers of the cell’s ATP requirements, there is increasing recognition that mitochondria regulate several aspects of cell function. This regulation is achieved by the ability of mitochondria to both import and export Ca²⁺ across the inner membrane, a feature that impacts on the cytosolic Ca²⁺ concentration, as well as to generate diffusible second messengers. The purpose of this symposium is to bring together speakers who can address different aspects of this novel hypothesis. Several kinds of physiological regulation will be considered. In hyperglycemia, mitochondrial overproduction of reactive oxygen species leads to vascular pathology (Brownlee). In capillaries subjected to pressure stress or cytokine infusion, mitochondrial reactive oxygen species induce proinflammatory responses (Bhattacharya). In lung, mitochondria act as oxygen sensors, generating reactive oxygen species that induce hypoxic vasoconstriction (Schumacker). In T cells, mitochondria control Ca²⁺ channel activity and thereby regulate T cell activation, hence immune function (Lewis). Although there has been a resurgence of interest in mitochondria, recent symposia and meetings have focused largely on the mitochondrial role in cell death. This symposium will bring together new and exciting research that directly addresses the novel and under-investigated issue of mitochondria as regulators of physiological function. The speakers will highlight the general nature of this regulation, pointing to new experimental strategies that may impact future research.

Role of the Transcription Factor, TonEBP/NFAT5, in Osmotic and Immunologic Stress
Chairs: M. Burg and J. Handler

TonEBP was cloned as a transcription factor responsible for increased transcription of genes that regulate accumulation of organic osmolytes in response to hypertonicity in renal inner medullary cells. Substantial progress is being made in elucidating the complex osmotic regulation of TonEBP. The identical transcription factor was also cloned by homology to the rel domain of the NFATs that are involved in inflammation. In T cells, in addition to its osmotic regulation, NFAT5 is also involved in immunological responses. This is an area in which rapid advances are being made that reveal exciting diversity in the function of this novel transcription factor.

Glucagon-like Peptide 2: Function and Clinical Application
Chairs: D. Burrin and K. Tappenden

In the last five years, glucagon-like peptide 2 (GLP-2) has emerged as one of the most intriguing and potent modulators of intestinal growth and function. GLP-2 is a member of a family of glucagon-like peptides that have a variety of important biological functions, not only within the gastrointestinal (GI) tract where they are produced, but also in the body as a whole in terms of carbohydrate metabolism and appetite regulation. GLP-2 is a gut peptide that is secreted in response to nutrient ingestion and has trophic and functional actions that are highly specific for the gastrointestinal tract. The biological actions of GLP-2 are mediated by a G-protein linked receptor that is localized to the gastrointestinal tract. However, the precise cellular localization of the GLP-2 receptor and complete identity of down-stream signaling pathways have yet to be established. GLP-2 has been implicated as a key endocrine signal involved in the nutritional regulation of intestinal adaptation under conditions of total parenteral nutrition (TPN) and massive small bowel resection. Treatment of TPN-fed animals with GLP-2 stimulates intestinal growth and prevents mucosal atrophy. Short-chain fatty acids (SCFA) also exert trophic actions under these conditions of intestinal adaptation. Moreover, the trophic effects of SCFA may be mediated indirectly via stimulation of GLP-2 secretion. Growing interest in GLP-2 also has been fueled by the prospect that it may become approved for widespread therapeutic use in treatment of short-bowel syndrome in adults. Recent clinical studies in short-bowel patients indicate that GLP-2 treatment improves clinical outcomes, such as nutrient absorption and weight gain.

Life to Death Decisions and the Fate of Apoptotic Cells
Chair: J. A. Cidlowski

Cell death, in concert with mitosis and differentiation, is a critical component of a cell life cycle in metazoans. Homeostatic control of cell numbers under both normal and pathological conditions reflects a balance between proliferation and cell death. It is now well appreciated that apoptosis or programmed cell death is the primary counterbalance to mitosis maintaining the constant approximately 100 trillion cells in adult humans. In addition, apoptosis has now been implicated in over 50 human diseases, ranging from AIDS to heart disease, to stroke. Furthermore, components of the cellular suicide process are now actively being pursued as targets for therapeutic intervention by numbers of pharmaceutical companies. Research in apoptosis has been one of the most actively investigated research areas for the past 5 years with over 10,000 papers being published yearly.

Redox Signaling of Angiogenic Response in the Heart
Chairs: D. K. Das and N. Maulik

Reactive oxygen species (ROS) is implicated in the pathophysiology of a variety of vascular diseases including coronary artery disease, arrhythmias, congestive heart failure, cardiomyopathy, hypertension, atherosclerosis and diabetes. Constitutive cellular protection against oxidative stress is provided by various intracellular antioxidants such as glutathione, -tocopherol and ascorbic acid and antioxidant enzymes that include superoxide dismutase (SOD), catalase and glutathione peroxidase (GSHPx). There is evidence to support that oxidative stress resulting from increased production of ROS causes a reduction of intracellular antioxidants in the vascular organs. Pretreatment of the hearts with antioxidants or antioxidant enzymes has been found to ameliorate ischemic reperfusion injury by reducing the formation of ROS.

Interestingly enough, the same ROS has been found to stimulate angiogenic response in the ischemic reperfused hearts. For example, following percutaneous transluminal coronary angioplasty (PTCA), angiographic restenosis is frequently observed in the lesions treated with stents. A recent study demonstrated that vessel wall thickening after in-stent restenosis was accompanied by extensive neovascularization, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) expression, iron deposits and epitopes characteristic of oxidative stress. This would tend to indicate that ROS causes tissue injury in one hand and promote tissue repair in another hand by promoting angiogenesis. Dichotomy in ROS behavior can be explained in the light of recent findings that ROS can function as signaling molecules. Evidence is rapidly accumulating to indicate that ROS can initiate a cascade of signal transduction process. Nitric oxide (NO) is a typical example – it is a highly reactive radical which functions as a signaling molecule. It has been reported that during myocardial adaptation to ischemia, NO plays a crucial role by initiating a cascade of signal transduction processes. ROS have also been found to function as signaling molecules during myocardial preconditioning against oxidative or hypoxic stress.

Many antioxidants can also function as signaling molecules. One typical example is polyphenolic antioxidants such as proanthocyanidins and resveratrol. These compounds have been found to trigger a survival signal to the cells by reducing proapoptotic factors such as Jnk and c-Jun. It seems likely that anti-angiogenic properties of thiol-containing antioxidants are due to their ability to counteract the angiogenesis process triggered by ROS. It is our hope that the symposium will discuss how redox signaling can regulate the angiogenic response in the heart.

Neuron-Glia Interactions in Nervous System Function
Chairs: B. Ransom and J. Deitmer

The interplay between neurons and glia in the nervous system is more complicated than previously envisioned. Glial cells have been implicated in a plethora of cellular functions related to neuronal migration/differentiation, metabolic support, synaptogenesis, neurotransmitter regulation, and extracellular ion homeostasis. Bruce Ransom will begin the symposium by with opening remarks about the role of glia in nervous system function followed by more focused treatment of the metabolic coupling the occurs between neurons and glia. Recent evidence suggests that astrocytes release substrates such as lactate, alanine and alpha ketoglutarate which can be taken up and consumed by neurons to generate ATP. Erik Ullian will then speak on the critical role glia play in the formation and maintenance of synapses in the brain. CNS synapse number and efficiency can be regulated by a number of soluble factors released by glia suggesting that this cell type may actively participate in synaptic plasticity in the nervous system. Ray Swanson will expand on this topic and discuss the mechanisms that glia can modulate neuronal activity by regulating neurotransmitter accumulation at the synapse. Glia have specific transport mechanisms that sequester both glutamate and GABA from the extracellular space. Recent studies have shown that that there is regulated release of neurotransmitters from glia implicating an important role of glia in chemical synaptic transmission. Joachim Deitmer will continue on this theme by describing how glia can modulate neuronal function by altering extracellular ion concentrations, specifically K⁺ and H⁺. Regulation of these ions may be of particular importance in medullary control of cardiorespiratory function and the development of epileptic foci in the brain.

Recent Advances in the Study of Intestinal Hexose Transport Proteins
Chair: R. Ferraris

The average daily Western diet contains over 300 g of carbohydrate, and carbohydrate consumption is expected to increase in the future. In this symposium, we will discuss recent advances and new controversies related not only to the contributions of various intestinal sugar transport systems to the total sugar load delivered to the bloodstream but also to the regulation of these transport systems by their substrates. Recent findings indicate that the control of expression of intestinal hexose proteins, both GLUTs (facilitated hexose transporters) and SGLTs (sodium-coupled glucose transporters) is regulated in far more complex way than previously expected. We will describe recent advances in our understanding of molecular and signaling mechanisms underlying intestinal sugar transport. We begin with recent work that support the well established roles of SGLTs and GLUTs in the absorption of hexoses, describe the potential contribution of SGLTs in the transport of water across the epithelium, and relate how the appearance of SGLTs and GLUTs are regulated during ontogenetic development. We continue with a new proposal that GLUT2, long considered to be responsible for serosally-directed basolateral sugar transport, may also be involved in the passive absorption of sugars across the apical membrane. We describe the signaling mechanisms regulating the transient appearance of this transporter in the apical pole and how this mechanism may explain gaps in our knowledge of transepithelial hexose transport. Finally, we present new evidence showing that there may be additional GLUTs or unsuspected routes for the exit of hexoses across the basal pole of the epithelium, and suggest future studies that may explain and even unify these various models of intestinal hexose transport.

Microcirculatory Society Young Investigators Symposium
Chairs: J. C. Frisbee and D. W. Stepp

The purpose of the "Young Investigator Symposium" is to spotlight outstanding young investigators making the transition from a sponsored position to an independent scientist. Five individuals at this stage have been identified and have been invited to present their novel, independent work to the larger research community. The issues about which these invited presenters will be speaking encompass a wide range of sub-topics in microvascular research, including electrophysiology (Heaps), cell:cell communication (Welsh), vascular reactivity (Tune), angiogenesis/microvascular networks (Price) and quantitative modeling of transport/exchange phenomena (Beard). It is anticipated that providing this opportunity for these young investigators will increase their exposure as the next generation of leading investigators of the microcirculation, and we believe that the quality of speakers and the diversity of topics should allow for a highly stimulating scientific session.

Molecular Regulation of Nitric Oxide Synthase Activity
Chairs: P. Ortiz and J. Sullivan

Nitric oxide regulates a number of processes in the kidney including renal blood flow, tubuloglomerular feedback and nephron transport. Numerous renal cell types express nitric oxide synthase (Nos) including tubular segments (Nos 1, 2, 3), the endothelial cells (Nos 3) and the macula densa (Nos 1). As originally described, the activity of constitutive Nos isoforms (Nos 1 and 3) were primarily regulated by changes in intracellular calcium concentrations while that of Nos 2 was primarily regulated by increases in transcription and translation. Advances in the study of Nos isoforms have revealed that our original ideas concerning the control of Nos activities were simplistic. Recently it has been demonstrated that the activities of the three Nos isoforms can be regulated through protein-protein interactions and that activation in many instances requires translocation form one intracellular compartment to another. Furthermore, the protein-protein interactions involving a Nos isoform and regulatory proteins depends on splice variants of the original mRNA. The purpose of this symposium is review the most recent advances in our understanding of how translocation and protein-protein interactions regulate Nos activity. Activation by calcium will not be discussed.

Peroxisome Proliferator-Activated Receptors (PPARs)
Chairs: Y. Guan and C. Sigmund

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear hormone receptor superfamily. PPAR has three isoforms designated PPAR, PPARß/ and PPAR. All three isoforms share similar protein sequence and structure, but they differ in tissue distribution, ligand selectivity and biological actions. As ligand-activated transcription factors, PPARs participate in a broad spectrum of biological processes including cell differentiation, energy balance, lipid metabolism, insulin sensitivity, bone formation, inflammation, and tissue remodeling. PPAR is the molecular target of the hypolipidemic fibrates including benzafibrate and clofibrate. In general, PPAR is expressed in tissues with high mitochondrial and ß-oxidation activity corresponding to its role in regulating lipid metabolism. In contrast, PPARß/ is ubiquitously expressed and has been suggested to be involved in bone formation, oocyte implantation and lipid catabolism. PPARß/ ligands have been found to improve lipid profile and insulin resistance and modulate cell survival. PPAR is a key player in adipogenesis and plays important roles in diverse cellular processes such as cell cycle regulation, cell differentiation, and insulin sensitivity. Synthetic PPAR ligands including thiazolidinediones (TZDs) and non-TZD compounds have been shown to increase insulin sensitivity and improve hyperglycemia in insulin resistance and insulin-independent diabetes mellitus (NIDDM). Based on biological effects of PPARs, both agonists and antagonists for PPARs may provide new therapeutic options in a variety of human diseases.

Recently, the kidney has also been shown to differentially express all PPAR isoforms. PPAR is predominantly expressed in proximal tubules and medullary thick ascending limbs, while PPAR is expressed in medullary collecting ducts, pelvic urothelium, glomerular mesangial cells and renal microvascular endothelial cells. PPARß is ubiquitously expressed in all nephron segments as well as interstitial cells. Accumulating data has begun to emerge suggesting physiological and pathophysiological roles of PPARs in the kidney. PPAR plays an important role in triggering fatty acid utilization and the adaptive response to dietary lipids in the kidney. PPAR may not only modulate vascular tone but also be a novel regulator of water and sodium homeostasis possibly accounting for water and sodium retention in patients receiving antidiabetic thiazolidindiones PPAR ligands. Glomerular PPAR has been found to participate in mesangial remodeling and might be a therapeutic target for treating glomerulosclerosis and diabetic nephropathy. Although PPARß is ubiquitously expressed in the kidney, recent data suggest an important role of PPARß in adaptive role for cells exposed to hyperosmality. Finally, PPARs also participate in lipid metabolism, inflammation, renal cell survival and apoptosis and blood pressure regulation and may be critical contributors in dyslipidemia, hypertension and atherosclerosis secondary to the renal diseases.

The aim of the symposium is to overview the current knowledge relating to PPAR action, ligand binding and tissue distribution. Recent developments regarding the role of PPARs in diabetes, inflammatory disease (atherosclerosis), hypertension, cell proliferation and differentiation and extracellular matrix remodeling with particular relevance to the kidney will be discussed.

Plasticity and Behavior
Chair: R. G. Guzmán

The symposium on Behavior and Plasticity focuses on several aspects of neural plasticity, such as 1) The increasing of dendritic branching produced by oxytocin in cells that innervate the pubococxigeus muscle in spinalized male rats; 2) The role of CCK in the development of preference for the mother of newborn lambs; 3) The protective effects of overtraining against experimentally-induced amnesia; 4) The interactions of striatal GABAergic and cholinergic systems modulating different aspects of behavior.

Making Science News
Chair: A. Gwosdow

Mapping the genome ... hypertension ... heart disease—the list of recent news stories written on science-based issues goes on and on. These articles are part of a growing niche in the media for science and health news. Journalists are eager to report on new research in the life sciences. Many reporters have a moderate knowledge of the sciences and some even have subscriptions to scientific journals. They are becoming more receptive to scientific information, especially that which affects human health and personal quality of life. A growing number of reporters have become proactive in their approach, contacting scientists to explore new research on the horizon.

What does this mean to APS members? This ever-expanding interest in scientific news is an opportunity to assist in public understanding of and garner public support for scientific and biomedical research. Not only are there many more occasions to publicize scientific studies, but there is also a higher probability that scientists will be called upon by the media to explain these studies. Helping scientists to take advantage of these opportunities is the aim of this EB 2003 Symposium organized by the APS Communications Committee.

The symposium, entitled "Making Science News," will feature a panel of three journalists (from TV, newspaper and radio) who will offer their insight into what makes science news and the best practices for getting scientific research covered. The symposium will also feature a hands-on session with medical publicist Donna Krupa about how scientists can work with the media. This will take the form of a mini-workshop where participants can engage in practical exercises.

The goal of this symposium is to familiarize scientists with how the media works. By preparing scientists to sculpt clear, media-ready messages, the scientific community assists in bringing accurate information to the public. The symposium is open to all.

Physiology in Medicine: Renal and Cardiovascular Pathophysiology
Chairs: J. E. Hall and D. J. Benos

The American Physiological Society, as part of its strategic planning activities, has embarked upon a translational physiology initiative. The APS defines translational research as "the transfer of knowledge gained from basic research to new and improved methods of preventing, diagnosing, and treating disease, as well as the transfer of clinical insights into hypothesis that can be tested and validated in the basic research laboratory." This definition explicitly states that translational research occurs in both directions, from the bench to the bedside and vice versa. To this end, we designed a symposium to highlight translational physiology in the general area of renal and cardiovascular disease. The symposium will examine specific issues within the topic area covered, and to facilitate a continuing dialogue between basic and clinical scientists. This Societal effort is a continuation of on-going efforts to publish translational research in all of the Society’s research journals, as well as in the Physiology in Medicine (PIM) series, published in Annals of Internal Medicine.

Peter Libby, M.D., Chief, Cardiovascular Division Harvard Medical School, will speak first. He will review the role of hypertension and inflammation in the process of atherosclerosis. The second speaker, Dr. Sanjiv Gambhir, M.D., Ph.D. (UCLA), is a leading scientist in the field of molecular imaging, including gene expression. Dr. Gambhir will present the therapeutic/diagnostic values of molecular imaging in cardiovascular disease. The third speaker, Dr. Friedrich Luft, M.D. (Franz-Volhard-Klinic, Berlin) will integrate mechanisms of diabetic and hypertension-induced nephropathy—the two main causes of end-stage renal disease. Lastly, Kathy Griendling, M.D. (Emory University), will discuss the clinically relevant topic of oxidative stress in cardiovascular disease. Speakers will emphasize the ways in which they developed their interdisciplinary research teams, and share their thoughts and experiences in this regard. They will not discuss details of these research topics, but rather highlight the "bridging" aspects necessary for successful translational research. They are all excellent speakers and their presentations will engender much interest.

Muscle Physiology: From Cellular to Integrative
Chairs: R. L. Hester and G. A. Ordway

Muscle physiology is an important component in the teaching of a number of organ systems and of the integration of these systems in response to environmental stresses. Purposeful movement, as well as normal cardiovascular, respiratory, and gastrointestinal function all depend on intact, healthy muscles. This unique refresher course will present up-to-date concepts in muscle physiology. The material will cover smooth, skeletal, and cardiac muscle, followed by an integration of these systems in the context of the physiological response to exercise.

Genomics of Angiogenesis and the Microcirculation
Chair: J. B Hoying

Considerable effort is being directed at understanding the complexities of the cardiovascular system. Many diseases involving the heart and vasculature are considered to have a polygenic etiology. Furthermore, it is thought that gene polymorphisms and varied gene expression levels explain a significant amount of the observed phenotypic variation and disease predisposition. Genomic-based research is providing the foundation to understand the molecular complexities of a number of vascular-related diseases including atherosclerosis and hypertension. Similarly, genomic and genetic approaches are being applied to the microvasculature in an effort to discern the molecular features of this dynamic section of the vasculature. Researchers are identifying new classes of genes and additional levels of molecular interplay in the areas of microvascular patterning and tissue vascularization. This session is intended to highlight these research efforts and provide a forum for continued discussion.

Caveolar Domains in Cell Signaling
Chair: P. A. Insel

There is a wealth of recent information that indicates that microdomains of the membrane, in particular caveolar microdomains, function as signaling organizing centers to regulate formation of key second messengers and their actions on enzymes and channels. Caveolins, proteins found in caveolae, seem to function as both scaffolding molecules and as regulators of enzymes involved in generation or action of second messengers. Speakers in this symposium will review some of the recent ideas that implicate such a central role for caveolae in signal transduction and cell regulation.

Thin Filament Regulation of Muscle Contraction
Chair: J.-P. Jin

Muscle contraction is regulated by Ca²⁺. This session will focus on the structure and function of the thin filament regulatory system in muscle. The discussion of striated muscle regulation will focus on skeletal muscle. The potential role of smooth muscle thin filament regulation will also be discussed. Striated muscle contraction is primarily regulated through the actin thin filament based troponintropomyosin system. Skeletal muscle contraction represents the basic mechanism of striated muscle function. The current model for skeletal muscle contraction proposes that excitation signal from a motor neuron induces depolarization of the plasma membrane of the muscle fiber at the neuromuscular junction. The resulting change in membrane potential triggers a rise of cytoplasmic [Ca²⁺]. Contraction is initiated by the binding of Ca²⁺ to troponin C (TnC, the Ca²⁺-binding subunit of troponin) and induces a series of allosteric changes in TnC, troponin I (TnI, the inhibitory subunit of troponin), TnT (the tropomyosin-binding subunit of troponin) and tropomyosin. These conformational changes in the thin filament allow the myosin head to form a strong crossbridge with F-actin. This activates the myosin ATPase and forces the thin filaments to slide relative to the thick filaments and shorten the sarcomere. Troponin and tropomyosin play central roles in this Ca²⁺-signaling mechanism. Therefore, their gene regulation, structure and interactions are critical to the function of muscle. A better understanding in this area will lead the studies of physiological adaptation of muscle and pathogenesis of myopathies. In smooth muscle, the primary regulation of contraction is through Ca²⁺-calmodulin-dependent phosphorylation of myosin light chain, which activates the actomyosin Mg-ATPase. However, during sustained contractions of tonic smooth muscle, force is maintained while [Ca²⁺] and myosin phosphorylation are reduced.

Therefore, it has been that additional regulatory mechanisms may exist at the level of the thin filament. For example, caldesmon and calponin inhibits the actin-activated Mg-ATPase activity of phosphorylated smooth muscle myosin and the inhibition is regulated by phosphorylation-dephosphorylation. The physiological role of the smooth muscle thin filament regulation has been a focus of debate and deserves further discussion.

The Drug Discovery Process: Opportunities for Physiologists
Chairs: J. H. Johnson and J. M. Norton

The purpose of this symposium is to expose young physiologists to new career opportunities, to educate others about the important work of the physiologist in drug discovery, and to demonstrate how academic collaboration with industry leads to new drug discoveries. The program will lead the audience through the drug discovery process from discovery of the initial drug target, to the role of the academic scientist, to the development of candidate drugs that have efficacy in a disease model, to preclinical safety, pharmacokinetics, pharmacodynamics, to various phases of clinical trials all the way to getting the new drug on the market. Each speaker will highlight the unique career opportunities at all levels for trained physiologists.

The Function and Regulation of Mitochondrially Produced Nitric Oxide in Cardiomyocytes
Chairs: A. J. Kanai and J. Peterson

Recent findings from a number of laboratories have demonstrated the presence of a constitutive nitric oxide synthase (NOS) in mammalian mitochondria (mtNOS) from brain, liver, kidney, skeletal and cardiac muscle. This was accomplished using cellular, organelle and enzyme preparations of mtNOS and a number of different NOS detection techniques. Furthermore, in cardiac myocytes, mtNOS has been identified as the -splice variant of neuronal nitric oxide synthase (nNOS). This was deduced by the direct microsensor measurement of nitric oxide (NO) production, which was absent in cardiac mitochondria isolated from the hearts of nNOS , but not eNOS or iNOS knockout mice. However, while the existence of mtNOS is now established, the function(s) of mitochondrially produced NO remain(s) controversial.

NO at nonphysiological millimolar concentrations has been known for many years to bind to cytochrome c oxidase, the terminal enzyme in the mitochondrial electron-transport chain. However, the more recent finding that physiological nanomolar concentrations of NO inhibit cytochrome c oxidase transiently and competitively with molecular oxygen indicates a potential physiological role for NO in the control of cell respiration, ATP synthesis and myocardial contractility. It is presently unclear whether the 10–20 nanomolar NO produced by mtNOS is adequate to inhibit cytochrome c oxidase significantly, or whether the 200–400 nanomolar NO produced in the cytosol or by the vascular endothelial cells is required. In addition, NO might also augment the generation of reactive oxygen species produced by the mitochondria and thereby trigger events leading to apoptosis. For example, complexes I and III of the mitochondrial respiratory chain are thought to be the principal sites of superoxide (O₂^-) generation in the cell. Typically, O₂^- is dismutated to hydrogen peroxide (H₂O₂) by manganese superoxide dismutase (MnSOD or SOD2) in the mitochondria. However, NO has been shown to react with O₂^- to form peroxynitrite (ONO₂^-), a strong oxidant that is thought to be responsible for the pathological actions of NO via protein nitration. It has also been suggested that cytochrome c oxidase possesses peroxynitrite reductase capabilities which may help clear this strong oxidant from the mitochondrion.

Accordingly, in this Symposium, we will discuss the characterization and biochemistry of mtNOS. The nitric oxide cytochrome c oxidase signaling pathway, its mechanism and biological implications. We will also discuss the mechanism and consequences of protein nitration in mitochondria and the possible consequences of MnSOD dysfunction for the cell.

NHLBI Program for Genomic Applications: Background for Physiologists
Chair: A. E. Kwitek Black

A major focus in health care in the new millennium will be to link genomic information to pathophysiology. The National Heart, Lung, Blood Institute (NHLBI) has pioneered a Program for Genomic Applications (PGA) (http://www.nhlbi.nih.gov/resources/pga/), a major initiative to advance functional genomic research related to heart, lung, blood, and sleep health and disorder. The program, consisting of 11 PGAs, will develop information, tools, and resources to link genes to biological function on a genomic scale. All the information, reagents, and tools developed in the PGAs will be freely available in a timely manner to the research community. This workshop, a follow up to an ASBMB supported PGA seminar (immediately prior), would provide the scientific community working in heart, lung, blood, and sleep disorders, how to utilize the resources developed by the PGAs, including animal models, DNA variations (SNPs), gene expression (microarrays), and bioinformatics.

Novel Ca²⁺ Signaling Mechanisms in Vascular Myocytes: Cyclic ADP-Ribose, Ryanodine Receptors and C²⁺-induced Ca²⁺ Release
Chairs: P.-L. Li and C. Van Breemen

Recent studies have indicated that a novel Ca²⁺ signaling pathway mediated by cyclic ADP-ribose (cADPR) and ryanodine receptors (RyR) plays an important role in the regulation of vascular tone. It has been demonstrated that this pathway is involved in generating Ca²⁺ sparks, waves and oscillations in cells, as well as in modulating Ca²⁺-induced Ca²⁺ release (CICR) and spontaneous transient outward currents (STOCs). It has recently been implicated in regulating vasomotor response to various agonists.

Despite intensive investigations regarding the actions of cADPR/RyR signaling in a wide variety of cell systems spanning three biological kingdoms; protist, plant and animal, its importance has not yet been widely recognized in the field of vascular physiology and pharmacology. The symposium will focus on the fundamental roles of this signaling pathway in regulating vascular tone and in mediating vasomotion in response to various agonists. We feel that it is important to promote discussions and exchange ideas between scientists with interests in the basic mechanisms of this novel signaling pathway and those with interests in vascular physiology and pharmacology. The cross-fertilization of ideas will greatly advance our understanding of the physiological and pharmacological relevance of this new Ca²⁺ signaling pathway.

Presentation Skills
Chairs: C. M. Liedtke, S. Benyajati, and J. Lakoski

One of the charges to the Women in Physiology Committee is to distribute information to young scientists regarding strategies for a successful career in science. Another is to coordinate activities with other such groups within FASEB. The APS Women in Physiology Committee is very pleased to jointly sponsor a workshop on "Presentation Skills" with the ASPET Women in Pharmacology Committee. APS co-chairs Carole Liedtke and Sinya Benyajati will coordinate planning with ASPET representative Joan Lakoski. The format of the workshop is to present four topics in15 minute talks followed by a breakout session. Topics include elements of good oral and poster presentations, how to share science with the public and media, and interviewing skills. Panelists will include, but not be limited to, APS and ASPET women in an effort to promote awareness of women who are successful scientists/role models. Tentative panelists include Joan Lakoski (Poster presentation), Mary Hendrix (Sharing Science with the Public/Media) and Kim Barrett (Oral Presentation). After the talks, a breakout session is planned to promote active participation of the audience and young scientists in best practices for each topic. The target audience is young scientists of both genders interested in learning skills for their future careers. The workshop also offers a venue for networking between junior and senior scientists.

Everything Old is New Again: Thyroid Hormone and the Failing Heart
Chair: C. S. Long

Although once used for patients with cardiac dysfunction, thyroid supplementation was dismissed as a viable therapeutic approach for these patients as newer pharmaceuticals became available and the untoward side-effects (tachycardia and increased myocardial oxygen consumption) became problematic. A possible role for thyroid hormone receptor therapy in patients with heart failure has undergone a recent renaissance as both basic science and clinical data have supported a possible connection between thyroid receptor isoform expression and the failing heart as well as the availability of analogs with both receptor specificity and limited myocardial side-effects. This symposium will review both the recent basic science and clinical advances that would support a role for modulation of the thyroid hormone receptor axis as a viable alternative (or supplement) to presently available therapies.

Subcellular Organization of Second Messenger Signaling in Cells of the Cardiovascular System
Chairs: R. Lynch and R. J. Paul

Over the last decade it has become appreciated that signaling cascades are organized within cells, and this organization confers advantages with respect to specificity in activation of cellular functions. This symposium would survey current work using a variety of techniques to investigate signaling pathways and their organization in cardiac and vascular cells. The topics will range from the organization of syub-membrane calcium stores and signaling to the dynamic regulation of protein kinase and G-protein interactions for localizing signaling events. This symposium would like draw individuals from a range of areas due to the general implications of the work.

Caveolin Regulation of Endothelial Function
Chairs: R. D. Minshall and A. B. Malik

There has recently been much interest in the function of caveolae driven by the findings that caveolae concentrate a variety of signaling molecules. Some of the interest has been sparked by the recent findings observed in caveolin^-/- mice. Caveolin-1 oligomerization and insertion in the cytoplasmic face of the plasma membrane not only serves as a scaffold and "master" regulator of signaling molecules, but also forms the ridges around the caveolae that enable invagination of the membrane into the flask-shaped caveolae structure. In this Symposium, the focus will be on the regulation of endothelial function by caveolin-1 from four perspectives: intra-cellular Ca²⁺ regulation, control of NO production, role in endocytosis, and signaling of cell proliferation. (1) Dr. Richard Anderson, a pioneer in the caveolin-1 field, will describe the regulation of Ca²⁺ signaling and Ca²⁺ entry by caveolin-1. As Ca²⁺ influx channels and pumps appear to be concentrated in caveolae, caveolin-1 may be key in regulating intracellular Ca²⁺ signaling in endothelial cells. (2) Dr. William Sessa will outline how caveolin-1 regulates nitric oxide signaling. In his model, endothelial nitric oxide synthase is held in an inactive conformation by the caveolin-1 scaffolding domain. An increase in cytosolic Ca²⁺ or activation of the kinase Akt can activate eNOS and lead to its dissociation from caveolin-1. (3) Dr. Richard Minshall will address his findings on the regulation of Src kinase signaling and dynamin activation by caveolin-1. In this context, tyrosine phosphorylation of caveolin-1 is a key "switch" regulating caveolae-mediated endocytosis and transcytosis of macromolecules in the endothelial barrier. (4) Finally, the phenotype of the caveolin-1 knockout mouse lung and endothelial barrier will be described by Dr. Radu Virgil Stan. The fibrotic lung observed in this model may be the result of an uncontrolled endothelial cell proliferative response that will be discussed in the context of the signaling mechanisms regulated by caveolin-1. Together, this Symposium would foster a better understanding of how caveolin regulates endothelial cell signaling and function.

Redox Regulation of Renal Function and Arterial Pressure
Chairs: R. D. Manning, Jr. and A.-P. Zou

Recent studies have indicated that physiological concentrations of reactive oxygen species (ROS) play an important role in the normal regulation of cell and organ function. Redox-mediated signaling is emerging as a fundamental regulatory mechanism in cell biology and physiology. In this regard, ROS have been reported to participate in the control of vascular tone, and the interaction of superoxide (O₂^-) and nitric oxide (NO) has been considered as one of the important mechanisms regulating cardiovascular function. It has been demonstrated that O₂^- inactivates the endothelium-dependent relaxing factor (EDRF), thereby reducing the arteriolar dilation to acetylcholine or other endothelium-dependent vasodilators. The production or scavenging of O₂^- may profoundly alter the levels and activity of NO in the vascular wall. This interaction of NO and O₂^- is of importance in the regulation of endothelial function and thereby in the control of vascular tone.

Despite intensive investigations of the physiological role of ROS in the control of vascular functions, the redox regulation of renal function remains poorly understood. Since more and more physiologists and other scientists are interested in this topic and many studies have been published in this area more recently, we feel now it is very timely to organize a symposium to present some new information and ideas about redox regulation of renal function and arterial pressure. Importantly, this symposium will mainly focus on physiology of ROS, rather than its pathological effects in the kidney, which will bring those scientists who are interested in basic function of ROS, together for discussion and exchange of ideas. We believe this symposium will largely increase our understanding of this new physiological mechanism regulating renal function or water and electrolyte homeostasis.

Regulation of Ion Channel Structure and Function by Reactive Oxygen Nitrogen Intermediates
Chairs: S. Matalon and D. C. Eaton

Ion channels are one of the major mechanisms for transducing external signals across the cell membrane to the cell interior. Therefore, intracellular signaling mechanisms that control the activity of ion channels are extremely important to normal cellular function and cellular homeostasis. Because of the importance of ion channels, many traditional cellular signaling mechanisms modulate ion channel function; however, role of reactive oxygen and nitrogen species have only recently been recognized for their role in altering ion channel activity. Ion channel modulation by reactive species can occur in several different ways. The simplest is through direct post-translational modification of the channel protein. Nitrosylation, nitration and oxidation of key amino acid residues are good examples of such a modification. Alternatively, reactive species can alter the activity of existing signaling mechanism that subsequently lead to changes in channel activity or channel gene expression. An example of this is the activation of the MAP kinase pathways by reactive oxygen species or the G kinase pathway by NO. Finally, there are other more complicated mechanisms mediated by reactive species that alter trafficking or turnover of channel proteins as typified by oxygen radical activation of NF-kB with subsequent changes in proteasomal degradation of channel degradation. Regardless of the mechanism, as will be discussed in this symposium, changes in the cellular level of reactive oxygen and nitrogen species can have profound effects on the activity of ion channels and cellular function. The four speakers will discuss their most recent findings concerning the effects of reactive oxygen nitrogen intermediates on calcium, potassium, sodium and chloride channels. This symposium will have wide appeal to a diverse audience.

The Pons: A Critical Component in Respiratory Control
Chair: D. R. McCrimmon

Evidence is substantial that pontine mechanisms play a fundamental role in the neurogenesis, control and modulation of eupneic ventilatory activity. From the day of birth, perturbations of pontile regions significantly alter the eupneic pattern. Moreover, pontine mechanisms have been implicated in the state-dependent control of breathing, as well as in the reflex protection of the airways. Nevertheless, the pontine roles in respiratory control are much less understood than those of the more accessible circuits in the medulla and spinal cord. The symposium will bring together participants who are internationally recognized for their expertise in differing aspects of pontine influences on respiratory control. Don McCrimmon will act as chair of the symposium and provide a brief introductory synthesis of the anatomy and proposed roles of the pons in respiratory control. As the first speaker, Nancy Chamberlin will lay out the anatomical foundations for interactions between parabrachial and Kolliker-Fuse nuclei in the dorsolateral pons with medullary cardiorespiratory regions. She will also introduce the inter-trigeminal region as an area with site-specific influences on respiratory motor output that may participate in airway defensive behaviors. Mathias Dutschmann will continue the discussion of the role of parabrachial and Kolliker-Fuse nuclei of the rostral dorsolateral pons with a consideration of the postnatal development of pontine structure and function. He will do this in a context of continuing the discussion of the pontine role in upper airway reflexes, including roles in the trigeminal (diving) and Breuer-Hering reflexes. Walter St. John, will develop the topic of respiratory-related rhythmic neuronal activity in the pons and the provocative concept that following removal of the medulla, the pontine circuitry is itself sufficient for generation of rhythmic respiratory activity. Finally, Ralph Lydic will conclude the discussion with a consideration of the pontine role in state-dependent changes in breathing and upper airway motor tone. He will present new work showing that significant changes in breathing and decreases in upper airway motor tone can be evoked from regions of the pontine reticular formation that modulate arousal but contain no respiratory neurons. In summary, a broad discussion is planned on the pons as a critical and relatively unexplored component of the brainstem ventilatory control system.

Mechanisms of Microvascular Dysfunction in Diabetes
Chair: P. F. McDonagh

Diabetes is increasing worldwide at an alarming rate. There are many serious complications associated with this disease. Many, including ischemic heart disease, stroke, peripheral vascular disease, renal failure and retinopathy, are related to microvascular dysfunction. Despite the importance of gaining a clear understanding of the pathobiology underlying the microvascular changes that occur in diabetes, the mechanisms are not clear. The aims of this symposium are to present the functional alterations that occur in the diabetic microcirculation and what is known about the mechanisms underlying these dysfunctions. Molecular, cellular, integrative and clinical perspectives of the diabetic microcirculation will be presented. Dr. Ritter will present an overview of microvascular failure in diabetes with attention to blood-blood vessel interactions under ischemic conditions in the coronary and cerebral microcirculations. Dr. Bohlen’s presentation will emphasize the effects of hyperglycemia and diabetes on endothelial cell function and microvascular blood flow. Dr. King will present alterations that occur in kinase signaling pathways, particularly PKC in diabetic microvessels. Dr. Tooke will discuss microvascular dysfunction in human diabetes and pre-diabetes, drawing on their more recent findings regarding microvascular hemodynamics in insulin resistant states. This comprehensive symposium will be of interest to experimental biologists, translational researchers and clinicians with an interest in the cardiovascular complications of diabetes.

The Teacher as Educational Researcher
Chairs: J. Michael and D. Silverthorn

For the teacher of physiology, the classroom offers a venue for research just as does the laboratory. Whether the questions being asked are purely local (what’s happening in my classroom) or more general (how can students be helped to learn this difficult concept better). There are a variety of approaches to educational research that can be pursued and a variety of kinds of data that can be generated. In this symposium we will discuss some of the issues that must be confronted once one decides to do educational research and we will offer some ideas about how to get started in this endeavor. The importance of this form of scholarly activity to the individual, to physiology, and to the broader field of science education will be discussed.

Oxidative Stress, Antioxidant Supplementation and Diabetes
Chair: E. C. Opara

Oxidative stress is defined as excessive production of reactive oxygen species (ROS) in the face of diminished antioxidant substances. It has been shown that oxidative stress, which increases with age, has an adverse effect on glucose metabolism, and is implicated in the etiology of both Type 1 and Type 2 diabetes. The development of disabling chronic complications of diabetes has also been attributed to oxidative stress. The body’s defense against oxidative stress is accomplished by interconnecting systems of antioxidant micronutrients (vitamins and trace elements) and enzymes. While the vitamins act as acceptors and donors of ROS, the trace elements regulate the activities of the enzymes. Although anecdotal reports indicate that the use of certain antioxidant micronutrient supplements may be beneficial as adjunct therapy in the management of diabetes and its complications, there is scarcity of data from well designed and controlled studies to support the empirical observations.

The purpose of this symposium is to review the role of oxidative stress in the pathogenesis of Type 1 and Type 2 diabetes, and in the development of major diabetic complications. In addition, the role of antioxidant supplementation as adjunct therapy in the management of diabetes and its complications will be highlighted. Given the increasing prevalence of diabetes, and the disproportionate health-care expenditures on the disease in the U.S., as in other countries, there is an urgent need to explore different therapeutic strategies to manage diabetes and its debilitating complications.

Functional Proteomics: Applications to The Cardiovascular System
Chair: P. Ping

The rapid development of proteomic technologies has recently enabled large pharmaceutical companies to inventory cellular proteins at an unprecedented rate. However, the tremendous amount of novel information obtained from such large-scale proteomic analyses awaits dissection and investigation. Functional proteomics aims to assemble and integrate proteomic information in order to understand the functional role of proteins in normal or diseased organs. This ability to characterize the intimate link between a cellular proteome and the genesis of a physiological/pathological phenotype presents the physiologist with new challenges and opportunities.

Transgenic Models of Heart Failure and Heart Failure Therapeutics
Chair: J. D. Port

During the past few years, there has been an explosion in the number of transgenic models of heart failure. Any number of proteins, either under expressed (knock out) or overexpressed, either wild type or mutant, have resulted in an apparent phenotypic endpoint of decompensated heart failure. Further, over or under expression of genes from a very diverse spectrum of classes can result in a highly similar pathophysiological endpoint. For example, over expression of several GPCRs, G-proteins, kinases, transcription factors, dominant negative kinases or transcription factors, as well as a number of sarcomeric or sarcomeric associated proteins, can all result in varying degrees of hypertrophy with or without progression too failure. This begs the question, which if any of these models recapitulates "real" causes of heart failure. Recently, several transgenic approaches, as well as gene therapy approaches, have shed light on possible gene targets that may "rescue" or attenuate the progression of the heart failure phenotype. Examples of these are overexpression of ßARKct and a phospholamban knockout. In each case, there is a hyperdynamic phenotype that when genetically crossed, "rescues" (selected) specific heart failure models without themselves promoting any detectable adverse side effects. The purpose of this symposium is to review certain genetic models of heart failure and to attempt to discern what "real" heart failure and what is not. Further, we hope to demonstrate how these models can be used to rescue heart failure with genetic approaches and contrast this to the traditional pharmacological approach. The hope is to translate these findings into a greater understanding of the molecular basis of heart failure and to identify, using genetic approaches, novel targets for the treatment of heart failure.

Functional Genomics and Proteomics of Hypoxia
Chairs: N. R. Prabhakar and J. Klein

An adequate supply of molecular oxygen is essential for the survival of mammalian cells. A decrease in oxygen availability i.e., hypoxia has serious physiological consequences. Physiological responses to acute hypoxia are rapid in onset and involve reflexes arising from arterial chemoreceptors. Whereas the responses to chronic hypoxia such as that occurs in many patho and physiological situations are delayed in onset and involves alterations in gene expression and protein function. With advent of new techniques for the analysis gene expression and protein function it is being increasingly appreciated that hypoxia not only affects multiple genes but more importantly alters the function of existing proteins. Furthermore, genomic analysis revealed that within a given species hypoxic responses vary among strains. This symposium focuses on recent advances in understanding the functional genomic and proteomic consequences of hypoxia. The presentation by Dr. Seta focuses on application of microchip analysis for studying gene expression by hypoxia. Dr. Baker’s presentation deals with functional genomic analysis of strain differences in the hypoxic response in rats. Unlike chronic sustained hypoxia, intermittent hypoxia leads to serious cardiovascular disturbances. The presentations by Drs. Klein and Kumar deal with how alterations in the expression and function of various proteins by intermittent hypoxia impact on physiological functions.

The Chronobiological Environment of Mammals
Chair: R. Refinetti

This symposium will highlight aspects of the chronobiological environment of mammals by examining comparative aspects of the influence of circadian rhythms on major physiological processes, particularly thermoregulation, sleep, reproduction, and feeding. The study of circadian rhythms has been one of the fastest growing fields in physiology during the last 20 years. An explosion of knowledge on molecular aspects of circadian rhythmicity has taken place in the last five years. The usefulness of knowledge about molecular mechanisms is tied to the understanding of gene expression and its specific role in the operation of physiological systems. Greater understanding of circadian modulation of physiological processes at the systems and whole-organism level in various species is necessary for a full integration of the growing knowledge on molecular mechanisms. The goal of this symposium is to bring together researchers who have been investigating the circadian modulation of physiological processes in a variety of mammalian organisms at the systems/whole-organism level and, by so doing, to facilitate the unveiling of general principles of circadian organization that control the operation of various physiological systems in various species.

Gap-Junctional Hemichannels: Physiology And Pathophysiology
Chairs: L. Reuss and L. Ebihara

Gap-junctional hemichannels (GJH) are formed when a connexon (connexin hexamer) inserted in the plasma membrane does not dock with another one in a neighboring cell. The unapposed connexon is a potential conductive pathway between the cell interior and the extracellular fluid. Under normal conditions hemichannels would be closed, largely because of the blocking effect of extracellular divalent cations, but in some instances also because of the membrane voltage and/or the level of phosphorylation of the connexin molecules. The "opening" of GJH threatens survival of the cell because these channels have high conductance to ions, with rather low selectivity, and are also permeable to hydrophilic solutes of Mr up to 1,000 Da. Thus, their activation causes dissipative plasma-membrane fluxes (e.g., uptake of Na⁺ and Ca²⁺, loss of K⁺ and ATP) that may not be compensated by the pre-existing membrane transport mechanism. Effects may be membrane depolarization, colloid-osmotic swelling, ATP depletion and increase in intracellular [Ca²⁺], which eventually may conduce to cell death. One of the main issues in this Symposium will be that ATP depletion (e.g., produced by ischemia) can activate GJH, which in turn cause or accentuate cell damage and thus act as "death channels." This, we propose, may be an important mechanism in brain, heart and kidney ischemic injury. The existence of GJH has been clearly demonstrated by their heterologous expression, but their very existence and possible role in native systems remains controversial. This symposium focuses on the arguments for the existence and pathophysiological role of GJH. Dr. Ebihara will discuss the properties of these channels in heterologous expression systems and the mechanisms of regulation of their permeability. Then Drs. Saez, Weiss and Vergara will present evidence for the existence of functional GJH in brain astrocytes, cardiomyocytes and renal epithelial cells subjected to "chemical ischemia", respectively. The brain, heart and kidney are the main organs in which connexin 43 (Cx43) is expressed. The three talks are expected to update the progress in this field in the last few years and should paint a consistent picture that assigns to GJH the potential role of death channels.

Magnetic Resonance: Unique Non-Invasive Insights into the Physiology of Exercise
Chairs: R. Richardson and M. Olfert

Magnetic resonance imaging (MRI) and spectroscopy (MRS) are both powerful methodologies offering the unique opportunity to non-invasively investigate both human biochemistry, human physiology and ultimately contribute significantly to the field of medicine. Consequently there has been much effort devoted to fostering the evolution of these methodologies into distinct and applicable techniques. Here we will highlight the physiological insight provided by several MRI and MRS techniques to better understand exercise related biochemistry and physiology. Specifically, the use of: 1) 1H MRS of myoglobin to assess intracellular PO2, 2) 31P assessment of muscle bioenergetics, 3) arterial spin labeling of muscle perfusion, and 4) functional MRI of muscle. This symposium will offer the audience a detailed sojourn into the non invasive world of MRS and MRI research, highlighting current discoveries as they pertain to the physiology of exercise.

The Renin-Angiotensin System and Development
Chairs: J. C. Rose and C. Rosenfeld

The symposium will focus on the renin-angiotensin system during development and will include presentations on the postnatal consequences of alterations in this system occurring prenatally. This approach will ensure that aspects of development will be related to adult physiology and pathophysiology. The topics that the speakers will cover span a broad spectrum under the overall theme of the symposium. The organization would be that the initial speakers would deal with ontogeny including aspects related to the regulation of gene expression and functional genomics of the components of the system. Subsequently, hormonal influences on the functional development of the renin-angiotensin system would be discussed. Here there would be an obvious link to the potential for translating research in the area. This would be followed by the importance of the renin-angiotensin system in the development of the kidney which would encompass both regulation of gene expression and translational research related to renal development. The last speaker would then address the general issue of prenatal influences on the renin-angiotensin system and their postnatal consequences on kidney function and blood pressure regulation with emphasis on the genesis of hypertension. This would provide a continuum linking the renin-angiotensin system with kidney development and with adult pathophysiology.

Flow/Stretch-Regulated Membrane and Ion Transport in Epithelia
Chairs: L. Satlin and G. Apodaca

Epithelial cells, which cover surfaces, line tubes, or form glands are exposed to various mechanical stimuli including osmotic or hydrostatic pressure, shear stress, and compression. Epithelial cells respond to these stimuli by modifying their rate of division, death, differentiation, movement, signal transduction, gene expression, secretion, and endocytosis. For example, in the cortical collecting duct of the kidney, flow-dependent changes in sheer stress and hydrostatic pressure are accompanied by changes in ion transport. The nature of the mechanical forces involved in these processes and the specific ion channels involved will be discussed by Drs. Satlin and Weinbaum. Dr. Welsh will describe the role of ENaC, degenerins, and sensory transduction. Mechanical forces also regulate exocytic and endocytic traffic in epithelial cells. In umbrella cells, which line the surface of the renal pelvis, ureters, and bladder, stretch stimulates vesicle exocytosis and endocytosis. The coupling of these events and the secondary messenger cascades involved in mechanotransduction will be presented by Dr. Apodaca. Stretch stimulates secretion of ATP in several epithelia, including those found in the kidney. Dr. Schweibert will discuss mechanisms of ATP release and the signaling that occurs upon ATP binding.

The History and Physiology of High Altitude Decompression Sickness
Chairs: S. Schneider and M. R. Powell

During exposure to hypobaric environments, individuals are exposed to a reduced ambient pressure, thus increasing the risk that inert gases may be expelled from body tissues in the form of bubbles and result in decompression sickness (DCS). To allow a safe exposure to a decrease in ambient pressure, the rate of pressure reduction must be controlled and/or appropriate countermeasures must be developed to reduce the rate of bubble formation or to minimize the physiological consequences. The first speaker, Dr. James Webb, will discuss the history, physiology, and prevention of DCS in aviators. The next speaker, Dr. Michael Gernhardt, will discuss the history of DCS during spaceflight, possible effects of microgravity on the occurrence of DCS, and the development and implementation of the current prebreathe countermeasures used by NASA to prevent DCS during space walks. These two presentations will be followed by short topics related to DCS, questions, and open discussion.

"IACUC 101" for Scientists
Chair: J. Stallone

The American Physiological Society in conjunction with the NIH Office of Laboratory Animal Welfare, American Society for Pharmacology and Experimental Therapeutics, American Association of Immunologists, American Society for Nutritional Sciences, American Association of Anatomists, and the Federation of American Societies for Experimental Biology will present a half-day program on the workings of the Institutional Animal Care and Use Committee (IACUC).

This program is specially adapted from the "IACUC 101" series developed by the Applied Research Ethics National Association (ARENA) and the American Association for Laboratory Animal Sciences. It is intended to address the concerns of research scientists. It will provide information useful both to scientists who serve on IACUCs and those whose protocols require IACUC review.

This is your opportunity to ask IACUC experts and representatives of regulatory authorities what the IACUC is actually required to do and how principal investigators are supposed to cope with these demands.

The quality of the oversight of research involving humans and animals is subject to scrutiny as never before. IACUCs have an enormous responsibility to ensure the humane care and use of laboratory animals. This symposium will provide concrete information about what IACUCs do and why along with the chance to request clarification on specific issues.

Neurogenic Hypertension
Chair: A. Sved

The central nervous system plays a large role in the control of blood pressure, and data from a variety of sources suggest that altered neural control of blood pressure may be a primary factor in hypertension. However, the extent to which hypertension is neurogenic is often debated. The goal of this symposium is to highlight the data demonstrating that human hypertension can be neurogenic, and to present recent developments on the central neurobiology of hypertension. The symposium will begin with a discussion of neurogenic hypertension from a clinical perspective, and then move through the interface of clinical hypertension with experimental models of hypertension, to the neural circuits driving increased sympathetic vasomotor outflow in experimental hypertension.

The Identities of Estrogen Receptors Mediating Nongenomic Effects
Chairs: C. S. Watson and P. W. Shaul

Cellular steroid receptor action has been thoroughly studied in the nuclear compartment. However, nuclear steroid receptor mechanisms have been unable to explain some of the rapid activities of steroids, particularly those that occur in a time frame of seconds to minutes. Based on these and other considerations, an alternative membrane-associated receptor form was proposed in the 1960s to mediate nongenomic steroid actions. Only recently have reports describing these receptors become more prevalent, because new experimental tools have been applied to identification of these proteins which mediate rapid steroid-induced actions.

The identity of the protein(s) mediating these responses is perhaps the most frequently debated question in this re-emerging field. There are several possibilities for classes of proteins which might mediate or participate in nongenomic steroid actions. These include: nuclear steroid receptor-like forms in nonnuclear locations, other known (non-steroid) membrane receptors with additional steroid binding sites, enzymes or transporters, receptors for serum steroid binding proteins, unique and previously undescribed proteins, or chimeras of a steroid receptor domains with other unique or known protein domains. This symposium session features examples from several of these categories, focusing on one hormone-binding class – the estrogens. Only further study and comparisons will reveal whether some or all of these explanations persist, and whether additional pieces of the puzzle will allow the merging of different hypotheses about the nature of these proteins. Interestingly, a few proteins have recently been reported to have dual identities. In addition, the partnering and clustering of proteins into functional units, and the mix-and-match nature of these associations to meet different cellular needs may also assist in understanding this story. Therefore, it is critical at this time to compare different examples and concepts about the nature of membrane steroid receptors.

New Roles for Ammonia in Renal Ion Transport
Chairs: I. D. Weiner and L. L. Hamm

Recent studies have identified exciting new aspects of ammonia-related physiology in the kidney. These include observations that ammonia regulates collecting duct transport of sodium, potassium and H/HCO3. Indeed, these observations serve to explain the decades-old observation that hypokalemia stimulates proximal tubule ammonia production. Studies have shown that increases in proximal tubule ammonia production cause decreases in urinary potassium excretion (human studies), that this occurs by decreasing net potassium secretion in the collecting duct (rat in vivo micropuncture studies), that ammonia both inhibits collecting duct principal cell-mediated potassium secretion (rabbit in vitro microperfusion studies) and stimulates collecting duct intercalated cell-mediated potassium reabsorption (rabbit in vitro microperfusion studies). Thus, ammonia may function as an intrarenal paracrine signaling molecule that serves to regulate potassium homeostasis.

In addition, ammonia also stimulates collecting duct proton secretion. These effects are independent of its role as a transported ion. Ammonia both stimulates unidirectional proton secretion and inhibits collecting duct bicarbonate secretion, and does so through a coordinated regulation of specific acid-base transporters. In particular, ammonia stimulates insertion of H-K-ATPase into the apical membrane of cortical collecting duct intercalated cells through stimulation of SNARE-protein mediated vesicular shuttling and membrane fusion. Thus, ammonia can also serve as a paracrine signaling molecule that regulates renal acid-base transport.

Last, a novel set of ammonium-transporting proteins has been cloned and shown to be expressed in the kidney. These proteins, Rh B Glycoprotein and Rh C Glycoprotein, are expressed in the convoluted tubule and the collecting duct, major sites for ammonium transport. Moreover, they are homologous with Rh A Glycoprotein, a component of the Rh complex on erythrocytes, and with ammonium transporters cloned from plants and yeast. The identification of these newly recognized proteins, that exhibit no significant homology with other known mammalian ion transporters, raises exciting new possibilities in the field of renal ammonia transport and metabolism.

AT-1 and AT-2 Receptors: Antagonists in Cellular Action?
Chairs: C. Sumners and M. Hay

Mammals contain 2 major subtypes of receptors for the peptide angiotensin II (Ang II), the AT-1 and AT-2 receptors. The AT-1 receptor is well known to mediate all of the classical physiological actions of Ang II, whereas the functions of AT-2 receptors are less well established. Recent studies have begun to uncover the physiological roles of AT-2 receptors, and in many cases it appears that they are opposite to the actions of Ang II via its AT-1 receptors, leading to the suggestion that these receptor subtypes have antagonistic roles in mammalian tissues. The overall goal of this Symposium is to address the issue of AT-1 and AT-2 receptor antagonism by describing up-to-date studies on these receptor subtypes, focussing on studies which indicate that they play opposite roles. Material covered will include data from molecular, genomic and physiological approaches, providing an analysis of these receptors and their interactions at the cellular and whole animal levels. The symposium will begin with a presentation by Sadashiva Karnik, who will give an overview of the structural and signaling properties of AT-1 and AT-2 receptors. This presentation will illustrate how different the AT-1 and AT-2 receptors are in terms of structure and signaling, and lay the groundwork for a presentation by Ursula Quitterer on the AT-2 receptor as an AT-1 receptor antagonist. Dr. Quitterer’s work will introduce the idea that antagonism between these receptor subtypes occurs at the level of receptor-receptor interactions rather than involving downstream signaling events. Colin Sumners will raise the issue of whether opposing AT-1 and AT-2 receptor actions are due to interactions at the post receptor level. To illustrate these points he will discuss the AT-1 and AT-2 receptors in central tissues, their opposing effects on signaling pathways and their counteracting electrophysiological responses. Helmy Siragy will deal with the issue of AT-1 and AT-2 receptors and their opposing effects at the whole animal level. His focus will be on the cardiovascular actions of Ang II, in particular the vasodilatory effects via the AT-2 receptor and how they may contribute to the control of blood pressure given the powerful vasoconstrictor actions of Ang II via the AT-1 receptor. The Symposium will be wrapped up with a brief presentation from Meredith Hay on the possible future directions of this field. The material covered in this Symposium will be of specific interest to investigators within the renin-angiotensin field of study, in particular those involved in the cell signaling, cardiovascular, renal and neural aspects. We also believe that this Symposium will be of broad interest to the Physiology community since it highlights new and controversial issues surrounding an important peptide, and displays how one peptide acting through two different receptors can elicit such dramatically diverse and opposite actions.

Remodeling of the Brain Underlies the Success of Behavioral Therapies for Motor Dysfunction
Chair: E. Taub

While studies over the past century have elucidated the mechanisms by which the central nervous system controls behavior, other experiments demonstrate that behavior has a profound reciprocal effect on the organization and function of the brain. This later findings are being successfully used to design new therapeutic approaches to motor dysfunction that are becoming effective first line methods for rehabilitation. The speakers in this symposium will detail the new insights that research in this area provides to our understanding of brain plasticity in the human. Massive reorganization occurs in the adult nervous system of animals and humans in response to both injury and increased use. M. Merzenich will demonstrate that the primary somatosensory and auditory cortical fields in intact, behaving rats and monkeys can be dramatically refined – or profoundly degraded— by specific forms of training, and he will elucidate the corresponding positive and negative plastic changes that occur in intact humans in response to dysfunction and intensive training-based remediation of dyslexia and other conditions. R. Nudo will illustrate functional reorganization in the intact motor cortex of adult primates after a focal lesion to the cortical representation of the hand. He will describe the relationship of these changes to behavioral recovery of manual skill during rehabilitative training. E. Taub will show in humans that Constraint-Induced Movement therapy (CI therapy) greatly enhances the amount of recovery of motor function in an affected upper extremity in patients with chronic stroke which persists for at least the two years measured to date. The treatment effect is associated with a large reorganization in the motor areas of the cortex. T. Elbert will present human imaging data indicating that massed practice leads to alterations in the functional organization of the cortex. This cortical reorganization can be adaptive or maladaptive. Focal hand dystonia, for instance, is related to a merging of the cortical representation of the affected digits. An effective treatment for focal hand dystonia is described that has the effect of separating the cortical finger representations. Together these speakers will demonstrate the powerful new insights that this area of research has provided to neuroscience, and in turn the clarity that modern neuroscience has provided to the mechanisms underlying these clinical approaches.

Non-Arterial Circulations: the Dark Side of Cardiovascular Biology
Chairs: S. Warburton and T. Wang

The vast majority of physiological investigations into circulation have focused on the high-pressure arterial system, and either ignored or gave a brief nod to other components such as the venous system, lymphatic system or the unique secondary circulation of fish. Most comparative treatments of circulatory regulation have focused on arterial pressure and the same can be said for evolutionary treatments. This trend persists, despite the fact that the importance of the Frank-Starling mechanism of intrinsic cardiac regulation has long been recognized. It seems imperative to begin a systematic dialogue on other components of circulatory systems and thereby formally recognize the arterial circulation does not function autonomously. The topics will include venous circulation in several vertebrate orders, lymphatic hearts and regulation, and the secondary circulation in teleosts. All the previous topics involve circulatory systems that are under some degree of regulation or potential regulation and are therefore potentially vital links in beginning to understanding the evolution of the cardiovascular physiology as an integrated system.

Section-Sponsored Featured Topics
Muscle Fatigue Chair: W. T. Ameredes

Tissue Response to Ischemic Injury: Adaptative and Rengenerative Strategies Chair: D. P. Basile

Integrated Cell Systems Chairs: J. Bassingthwaighte and A. D. McCulloch

Developmental Plasticity of Respiratory Control Chair: R. W. Bavis

Evolution of Vascular Regulation from the Neonate to the Aging Adult: Mechanisms and Functional Consequences Chair: M. A. Boegehold

Central Neurons and Efferent Pathways Controlling Thermoregulation Chairs: J. A. Boulant and K. Kanosue

Cardiovascular Physiology: from Bench to Classroom Chairs: R. Bukoski and C. Seidel

Development of Excitation-Contraction Coupling in the Embryonic Heart: from Simplicity to Complexity Chair: T. L. Creazzo

Oxidant Mechanisms in Neural Regulation of Cardiovascular Function Chair: R. L. Davisson

Bern Lecture Featured Topic: Control of Coronary Blood Flow Chair: E. O. Feigl

Therapeutic Potential of Hypothermia: Bridging the Gap between Clinical and Basic Thermoregulatory Research Chairs: C. Gordon and M. Dae

Functional Brainstem Anatomy: Can We Tell Cardiovascular and Respiratory Neurons Apart? Chair: P. Gray

The Lung—A Very Special Place for Dendritic Cells Chair: G. Grunig

Interaction between Histone Acetylation and DNA Methylation Chair: A. Guidotti

Intermittent Hypoxia: Physiological and Genomic Consequences Chair: G. Haddad

Causes and Consequences of pH Variability in Vertebrates Chair: L. Hartzler

Glial/neuronal Bi-directional Signaling Chair: G. Hatton

Preconditioning of Myocardium against Infarction Chairs: F. Kehl and D. C. Warltier

Epithelial Anion Channels: Structure, Form, Function Chairs: K. Kirk and C. Fuller

Structure and Regulation of Epithelial Na and K Channels Chairs: T. R. Kleyman and D. C. Eaton

Reflex Regulation of Airway Function and Breathing Chairs: L.-Y. Lee and B. Canning

Wiggers Award Featured Topic: Nitric Oxide and the Cardiovascular System Chair: A. W. Lefer

Neurohumoral control of body fluid volume and arterial pressure Chair: T. Lohmeier

AstraZeneca Young Investigator Featured Topic Chair: J. Miner

Is it the Physiology, the Students, or is it Me? Reflections on the Classroom Chair: H. Modell

Trafficking of Membrane Transporters in the GI Tract and Beyond Chair: C. Okamoto

Comparative Aspects of the Hormonal Responses to Metabolic Demands Chair: R. M. Ortiz

Identifying Genes and Targets in Cardiovascular Autonomic Pathophysiological States Chair: J. Paton

Regulation of Vascular Smooth Muscle Cell Phenotype: Contractile versus Proliferative Chair: U. Raj

Insights on Renal Function and Blood Pressure Control from Genetically Manipulated Animals Chair: R. Roman

Starling Lecture Featured Topic: Hypertension Chair: R. Roman

The Molecular Physiology of HCO₃^- Transport Chair: M. Romero and M. O. Bevensee

New Insights on Neuro-immune Interactions in Autonomic Regulation Chair: Y. Tache

Hypoxic Metabolic Response: Autoregulation, Acclimation and Adaptation Chair: G. Tattersall

Arteriogenesis and Collateralization Chair: J. L. Unthank

Regulation of Ion Transporter Trafficking Chair: W. Wang

The Regulation of Sympathetic Nerve Activity in Chronic Heart Failure Chair: I. Zucker

Physiology In Focus
Physiological Implications of Oxidative and Nitrosative Stress Organizer: B. A. Horwitz

General Overview and Disease Relevance Chair: M. Grisham

Emerging Concepts in Oxidative and Nitrosative Signaling Chairs: J. Beckman and Y. Jannsen-Heinenger