Department of Physiology
While other basic and clinical sciences analyze the molecular and cellular structure of systems and the effects of biological processes, physiology encompasses all of these, integrating myriad facets and layers of scientific scrutiny in the complex function of living organisms.
Thomas H. Hintze, Ph.D., Professor and Chairman, says that research in the Department of Physiology can be divided into two broad categories: cardiovascular and neurophysiological. Of the former, Dr. Hintze says, "More than half of all deaths [in the U.S.] are associated with heart disease or vascular-related conditions such as stroke, kidney disease and diabetes. Some of our researchers study normal and disease models of cardiac function, such as heart failure and hypertension, in relation to aging, exercise level and family history. Others examine endothelial and vascular smooth muscle cells—either freshly harvested or grown in culture—as well as the regulation of blood pressure and blood flow." Dr. Hintze is exploring the theory that reduced production of nitric oxide in blood vessels of the heart contributes to cardiac complications associated with heart failure and diabetes. To determine the role of exercise in improving the outlook for patients with cardiovascular disease, the group has been examining the beneficial effects of brief periods of moderate exercise, which are thought to increase nitric oxide production. Their studies have shown that enhanced nitric oxide production improves the effectiveness of certain drug therapies, including ACE (angiotensin converting enzyme) inhibitors and releasing factors known as statins.
Zsolt Bagi, M.D., assistant professor, is investigating the function of human coronary microvessels obtained from patients with diabetes mellitus, heart failure or hypertension. He is also using intravital microscopy and in vitro video-microscopy to study microcirculatory pathophysiology and pharmacology in animals suffering from these diseases and disorders. The lab evaluates overall cardiac contractile performance in animal models using non-invasive echocardiography and invasive catheterization techniques. With these preparations the team can make a detailed quantitative analysis in a well-defined and physiologic system. Dr. Bagi aims to develop greater understanding on how cardiovascular function is controlled in health and disease and how behavior affects overall organ function, in the hope of discovering new avenues for pharmacological interventions.
John Edwards, Ph.D., assistant professor, points out that cardiovascular disease is the leading cause of mortality in noninsulin-dependent diabetes mellitus patients. Diabetic cardiomyopathy is associated with abnormal cardiac function, increased apoptosis and loss of cardiac mass. Mitochondrial dysfunction has a significant role in the development and complications of diabetic cardiomyopathy. Diabetes elevates oxidative stress, which contributes to mitochondrial dysfunction. Mitochondrial DNA (mtDNA) is particularly susceptible to damage, and the laboratory group has demonstrated that increased mtDNA mutations are concomitant with the oxidative stress associated with hyperglycemia. The group is examining whether diabetic-induced alterations in mitochondrial topoisomerase activity are the underlying mechanism for mtDNA damage and mitochondrial dysfunction that is antecedent to heart failure. A second project will establish whether cardiac progenitor cells are more sensitive to chronic elevations in oxidative stress than cardiomyocytes. Taking a longer view, identifying the pathology of cardiac stem cells as a consequence of diabetes will alter the clinical paradigm for the management of diabetes. It will provide a basis for development of new studies that focus on the protection of stem cells as a real target for clinical management.
Carol A. Eisenberg, Ph.D., associate professor, studies the potential of adult tissue-derived stem cells to form myocardial tissue. Research in her laboratory focuses on three interrelated topics: (a) the development of culture conditions that would allow stem cells to give rise to pure cellular populations of differentiated tissue, (b) examination of the capabilities of bone marrow cells to produce functional cardiac tissue, and (c) the origins and phenotypic potential of stem cells obtained from the adult heart. The long-term goal is to develop procedures that would allow adult stem cells to be used as a source of fully differentiated cells for transplantation.
Leonard M. Eisenberg, Ph.D., associate professor, investigates molecular mechanisms that control the phenotypic direction of differentiating stem cells. One group of molecules that plays an important role in regulating cell fate decisions of stem cells is the WNT family of secreted signaling proteins. WNT regulation is essential for brain, limb, kidney, mammary gland, muscle and heart development. Disregulation of these molecules has also been shown to play a major role in tumor formation. Ongoing investigations in the laboratory concern how WNT signal transduction shift cell lineage decisions among alternative cell fates, and modulate the signal transduction pathways of other growth factors in regulating lineage determination among stem cells.
An Huang, M.D., Ph.D., assistant professor, is focused on the gender specific regulation of endothelial function of arterioles via nitric oxide (NO)-dependent and independent mechanisms, as a function of shear stress, especially, the signaling cascades responsible for the estrogen-specific regulation of shear stress by a cytochrome P450-dependent mechanism. Experiments are mainly conducted on microvessels (~100-200 µm) isolated from skeletal muscle, mesentery and coronary vascular beds of rats and mice. The functional changes involving vasodilator and constrictor responses are assessed. Also, experiments aimed to clarify possible mechanisms are performed by using molecular (PT-PCT, Western) and biochemical (HPLC, GC-MS) analyses, and transfection methods (si RNA) in the isolated vessels.
Akos Koller, M.D., Ph.D., professor, studies blood circulation and the effects of naturally occurring substances such as estrogen, nitric oxide, calcium and prostaglandins on the function of arterioles, capillary veins and lymphatic vessels. By studying the endothelium and smooth muscle of blood vessels, and probing cellular mechanisms that govern pressure and flow signals, Dr. Koller and his team may provide new clues to improve treatment of hypertension, arteriosclerosis and diabetes.
Christopher S. Leonard, Ph.D., professor, is focused on understanding how neurons communicate. Using sophisticated biophysical recording techniques as well as computer modeling, the group examines how neurons in the brain stem and cerebral cortex generate electrical impulses, and how these neurons and their synaptic interactions are modulated by neurotransmitters. Dr. Leonard aims to correlate current cellular studies with the system-level behavior of neurons—processes that regulate how the brain stays awake, sleeps and generates dreams.
Edward J. Messina, Ph.D., professor, is investigating the influence of hormonal, metabolic, myogenic and flow-dependent responses on the regulation of blood flow in skeletal muscle and fat. The myogenic response is the constriction of a blood vessel brought about by increases in blood pressure; flow-dependent dilation is the opposing influence induced by the flow of blood through the vessel. Using in vivo and in vitro studies of arterioles, the group is exploring ways in which disturbances in regulatory processes contribute to the vascular signs and symptoms associated with diabetes mellitus and hypertension.
Caroline Ojaimi, Ph.D., assistant professor, uses gene array technology and functional genomic approaches in vascular biology. Specifically, she aims to explore the differences in gene expression of the normal and diseased heart in animal models. Her emphasis is on identifying pathways of gene regulation, which may be responsible for the altered expression of eNOS and other functionally realted enzymes. The functional genomic approach is being applied to elucidate the critical role played by eNOS associated molecular alterations in heart failure and in different metabolic diseases that lead to cardiovasular dysfunction.
William N. Ross, Ph.D., professor, and his colleagues are studying the detailed interactions between neurons in the hippocampus and the cerebellum. Their primary focus is the complex system of dendrites, branch-like extensions of neurons where inputs from different parts of the brain come together and are integrated. Using a combination of electrophysiological and imaging techniques that allows them to view a wider landscape of dendritic events, the team is studying the role of neurotransmitters and receptors in controlling the release of calcium from neurons.
Dong Sun, M.D., Ph.D., associate professor, is mainly focusing on the regulation of endothelial function of arterioles. In particular, endothelial compensatory mechanisms in response to an impaired endothelial nitric oxide (NO) signaling and endothelial deformation-induced initiation of NO-dependent vascular protective mechanisms are studied. In recent years, he has focused on endothelial dysfunction of microvessels in response to vascular aging. Using isolated arterioles to assess flow-induced dilation and shear stress-induced release of NO, I demonstrated that age-associated endothelial dysfunction is characterized by an impaired NO bioavailability, due to a decreased shear stress-induced eNOS phosphorylation, an increased superoxide formation and a decreased antioxidant capacity. The increased superoxide formation in aged vessels is a consequence of eNOS uncoupling and increased expression of NADPH oxidase.
Michael S. Wolin, Ph.D., professor, is exploring how oxidants and nitric oxide interact with vascular signaling systems to control mechanisms in coronary and pulmonary arteries. Recent studies have underscored the fundamental role of oxidant-signaling mechanisms in cardiovascular disease. By examining oxidant-producing enzymes that act as sensors in detecting oxygen levels, they are improving understanding of how reactive oxidants affect enzymes known to interact with mechanisms that regulate blood vessel contraction and relaxation within a single cell or between neighboring cells of the endothelium and vascular smooth muscle.