The underlying questions under investigation in our research laboratories address the regulation of the cardiovascular system and the kidney by circulating hormones and biologically active arachidonic acid metabolites derived from cytochrome-P450 enzymes. Our researchers are particularly interested in how such systems relate to the development of hypertension, stroke and vascular changes associated with inflammation. This research is funded by a variety of extramural sources (National Institutes of Health, American Heart Association, etc.) and the Department has had a continuously funded NIH Program Project Grant on the Hormonal Regulation of Blood Pressure since 1985.
A fundamental goal of the pharmacologist is to better understand the biochemical and physiological mechanisms regulating organ functions, and the nature of the abnormalities which underlie pathological states—for example, hypertension or cancer. Such information lays a foundation for the development of new therapeutic drugs and is critical to understanding how drugs produce beneficial or toxic effects.
In the Department of Pharmacology, the underlying questions under investigation in our research laboratories address how hormones and neurotransmitters regulate specific organ functions, and their role in disease states and drug responses. A variety of organ systems are examined to address specific medical problems, but a major focus of the department has been studies on the cardiovascular system and the kidney.
Summary of Research
Lars Bellner, Ph.D.,instructor, uses in vivo and in vitro models to investigate the role of the heme oxygenases, particularly heme oxygenase 2, in corneal wound healing. Like the dermis, the cornea is constantly exposed to the elements, but unlike the dermis the cornea is and has to remain avascular in order to maintain the visual axis. The heme oxygenase enzymes are critical for the resolution of inflammation and to maintenance of cellular and tissue homeostasis.
Mairead A. Carroll, Ph.D., professor, examines the regulation of a recently discovered class of hormone-like factors, generated from arachidonic acid by cytochrome-P 450 enzymes, that affect blood vessel function and sodium transport in the kidney. Her team conducts experiments that probe the effects of cardiovascular hormones on levels of arachidonic acid and their derivatives in the kidneys. Their studies aim to clarify the role of arachidonic acid in the regulation of sodium excretion and the development of hypertension.
Nicholas R. Ferreri, Ph.D., professor, uses specific types of cells isolated from the kidney and blood vessels to clarify how their function is regulated by hormones in the development of hypertension and cardiovascular disease. Study of these cells, which are critical to the maintenance of normal blood pressure, may provide insight into how severe alterations in blood pressure and vascular function can be prevented or controlled.
Austin M. Guo, Ph.D., assistant professor, focuses on understanding the complex mechanisms involved in the regulation of the angiogenic processes necessary for tissue repair (re-vascularization) and cancer growth. Stem cells are used in my lab to investigate the role of cytochrome P450 derived eicosanoids, specifically 20-hydroxyeicosatetraenoic acid (20-HETE), in regulating the migration, homing and differentiation of endothelial progenitor cells to form a mature and functioning blood vessel.
Sachin Gupte, M.D., Ph.D., associate professor, studies the metabolic adaptation-cardiovascular function relationship in novel animal models and in vitro systems that mimic human diseases and to explore novel therapies for PAH and MS-CAD. Another objective of our lab is to develop stem cell-based technology to prevent contractures and facilitate angiogenesis in combat-related burn injuries.
Mario A. Inchiosa, Jr., professor, conducts much of his research in collaboration with the Department of Anesthesiology. His lab is investigating reflex sympathetic dystrophy, a condition also known as complex regional pain syndrome, which sometimes occurs in patients following apparent full recovery from trauma to the hand, wrist, foot or ankle. His hypothesis is that in some patients, sensory pathways that conduct pain perception have become exaggerated or “supersensitive,” a condition believed to be induced by catecholamines (epinephrine and norepinephrine). Dr. Inchiosa and his colleagues have tested the clinical effects of the drug phenoxybenzamine, a little used antihypertensive, that can produce a long-term block of some of the effects of catecholamines. The research is designed to discover ways of reversing the supersensitive state that causes the very painful syndrome.
Houli Jiang, M.D., Ph.D., assistant professor, conducts research on red blood cell-derived lipid mediators in the regulation of the circulation. Erythrocyte-derived epoxyeicosatrienoic acids (EETs) contribute to the vasodilation, anti-inflammation, and anti-aggregation. His research has identified mechanisms of the formation, release and hydrolysis of EETs by red blood cells. Stimulation of erythrocyte-derived EETs protects the cardiovascular system from atherogenesis, while inhibition of EET hydrolysis reduces blood pressure in hypertension. Regulation of these erythrocyte functions may have potential implications in the management of hypertension and other cardiovascular diseases.
Daohong Lin, Ph.D., assistant professor, explores the role of microRNA in the regulation of Kir channels such as Kcnj10 in renal epithelial cells. We apply molecular biological approaches and patch-clamp to identify the mechanisms by which K channels are controlled under dietary potassium restricted condition, therefore examine the critical role of K secretion in modulating blood pressure. Our group also investigates the role and regulation of KCNJ10 modulated my miR-205 in wound healing of the corneal epithelial cells.
Alberto Nasjletti, M.D., professor, directs the College’s first NIH program project grant, Hormonal Regulation of Blood Pressure, continuously funded since 1985. This wide-ranging project involves the investigation of vascular and renal mechanisms underlying the development of hypertension and associated disorders. Dr. Nasjletti’s distinguished scientific contributions have earned him an NIH MERIT award and he is currently the vice chairman of the American Heart Association’s Council for High Blood Pressure Research. Exploring the physiological processes underlying hypertension, Dr. Nasjletti’s team conducts experiments that focus on interactions between hormones and neurotransmitters that act directly on blood vessels. He is particularly interested in prostanoids, fatty acid derivatives affecting vascular function, and their role in hypertension due to elevations in angiotensin, a peptide hormone. Other studies explore the role of carbon monoxide produced by the blood vessels as an inhibitory regulator of vascular reactivity to factors that raise blood pressure.
C. Andrew Powers, Ph.D., associate professor, conducts research on endocrine pharmacology and is currently investigating the biological properties of C-terminal fragments of the pituitary hormones prolactin and growth hormone.
Petra Rocic, Ph.D., associate professor, studies the vascular complications of metabolic syndrome, including impaired coronary collateral growth. The aim of these studies is to elucidate signaling pathways and cellular processes which are necessary and sufficient for vascular growth and remodeling in normal, healthy animals, and determine how they are altered in metabolic syndrome in order to develop treatment paradigms to restore normal vascular function in metabolic syndrome.
Michal L. Schwartzman, Ph.D., professor and chair, conducts research on eicosanoids from two angles. Her lab is investigating the way certain types of these hormones contribute to the development of severe eye problems following injury or surgery, impairing healing and triggering inflammation and abnormal blood vessel growth. She also studies how a specific eicosanoid (20-HETE) contributes to the development of hypertension and resulting vascular, heart and kidney injury. The experimental approaches are multi-faceted and include the use of transgenic mice and genetically modified rats as well as molecular and pharmacological probes together with cell culture models.
Charles T. Stier, Jr., Ph.D., associate professor, conducts studies on hypertensive, stroke-prone rats to elucidate the hormonal and cellular mechanisms that hypertension contributes to blood vessel damage. His earlier work has led to the finding that kidney damage and stroke in these rats might be prevented by drugs that can inhibit the formation and interaction of the hormones angiotensin and aldosterone.
Wenhui Wang, M.D., professor, studies potassium channels—proteins found in the kidney that play an important role in regulating the blood levels and urinary excretion of electrolytes essential to normal cellular activity. Experiments in his laboratory employ electrophysiological techniques such as voltage clamp and patch clamp, as well as molecular biology to investigate the regulation of potassium channels by hormones that contribute to hypertension and other cardiovascular diseases.
Frank Fan Zhang, M.D., Ph.D. assistant professor, conducts research in the role of endogenous carbon monoxide and fatty acid in regulation of circulation and renal function. Dr. Zhang’s work was well received, and he was selected to receive a Merck New Investigator Award from the American Heart Association Council for High Blood Pressure Research since 1998.