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 vasculature, heartand the kidney.
Investigators are particularly interested in how the interactions between circulating hormones, autacoids and cytochrome P450-derived eicosanoids impact the development of hypertension, stroke and vascular changes associated with inflammation. Another major focus is related to the impact of obesity/metabolic syndrome on immunity, the cardiovascular system and pathological conditions including heart failure, pulmonary hypertension and atherosclerosis. The research programs in the Department are funded by various intramural and extramural sources (National Institutes of Health, American Heart Association, etc.). Translational aspects of the research programs in the Department are exemplified by fostering collaborations with clinicians through specific IRBs that allows for procurement of specimens to identify biomarkers and/or causative factors in diseases
Summary of Research 2018
Nader G. Abraham, Ph.D., Dr. H.C., FAHA, professor of Medicine and Pharmacology, research interests focus on functional regulation of antioxidant genes, heme oxygenase (HO-1), cytochrome P450-derived epoxides (EETs) and the PGC1a system in relation to pathophysiology of hypertension, metabolic syndrome and anti-diabetes. This research addresses human fat and mice primary stem cell-derived adipocytes and in vivo studies in animals subjected to genetic manipulation of HO-1, PGC-1a and cyp-genes. Special consideration gives way to examining the signaling mechanism underlying the biological response obtained by such experimental manipulations. The long-term goal of this project is to identify how the antioxidant genes and vasodilator signals interact to bring about defense system that afford protection against the detrimental metabolic and cardiovascular effects of obesity with an eye on identification of new therapeutic drugs to mitigate obesity and associated
Salomon Amar, DDS, Ph.D., professor. My research team has a long-standing interest in periodontal tissue homeostasis and mechanisms of inflammatory bone loss. Both basic immunological and translational research (including clinical trials) have been used to dissect molecular immune mechanisms and test them in animal models and ultimately in clinical trials. Our work has led to seminal observations in periodontal systemic diseases especially cardiovascular diseases or obesity leading to innovative approaches in public health aspects of these diseases. Our publication record includes several papers with an impact extending beyond the periodontal research field (e.g., in PNAS; J. Immunol. Circulation) and our work is highly cited (Google Scholar citation counter: Citations= 7153, H-Index=45; i10-index=87). Concepts first identified in the context of periodontal inflammation and immune tolerance have found application in other fields; for instance, our observation that high fat diet modulate the immune system in periodontal disease was extended to obesity to explain the diet induced immune dysregulation mediated by TLR2. I have successfully directed several NIH-supported projects that have implicated important components of innate immunity (Toll-like receptors and NOD) in novel mechanisms of inflammation and periodontal disease pathogenesis. We gained over the years, expertise in innate immunity, inflammation and obesity and contributed to the understanding of the role of infection in the modulation of Obesity, Cardiovascular disease, and Diabetes with a seminal paper in 2007 demonstrating that obesity interferes with the ability of the immune system to appropriately respond to infection.
Lars Bellner, Ph.D., instructor, uses in vivo and in vitro models to investigate the role of the heme oxygenases, particularly heme oxygenase 1, and eicosanoids, particularly Cytochrome P450-derived eicosatrienoic acids (EETs), in chronic inflammation, obesity and cardiometabolicsyndrome. There is a strong association between obesity and chronic inflammation. The heme oxygenase enzymes are critical for the resolution of inflammation and to maintenance of cellular and tissue homeostasis and the heme oxygenase-EET axis provides protection in adipose and cardiac tissues and preserves heart function, thereby attenuating myocardial infarction (MI) and heart failure.
Nicholas R. Ferreri, Ph.D., professor, We are studying the effects of TNF produced within the kidney on adaptive mechanisms that control sodium and chloride reabsorption and blood pressure. We have developed precision tools that allow us to target TNF in specific renal and inflammatory cell types using a lentivirus strategy in combination with cell-specific genetic deletion models of TNF. We expect our studies to contribute novel insights into how TNF acts as an autocrine regulator of renal function and blood pressure regulation.
Victor Garcia, Ph.D., assistant professor, focuses on characterizing the relationship between the vasoactive eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE) and the orphan receptor GPR75 with the pursuit of deorphanizing GPR75 as the 20-HETE receptor (20-HETER). The 20-HETE/GPR75 pairing and array of signaling mechanism influenced by this interaction is explored across the vasculature with a focus on endothelial and vascular smooth muscle signaling. Exploration within this topic will help shed light into various pathologies influenced by 20-HETE, including diabetes, metabolic syndrome, vascular remodeling and hypertension.
Austin M. Guo, Ph.D., assistant professor, investigating the complex mechanisms involved in the regulation of the angiogenic processes necessary for tissue repair (re-vascularization) and cancer growth. Stem cells and animal models are used in my lab to study the novel role of cytochrome P450 derived eicosanoids, specifically 20-hydroxyeicosatetraenoic acid (20-HETE), in regulation of the ischemia-induced angiogenesis involving endothelial progenitor cells, and its underlying molecular and cellular mechanisms.
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., Ph.D., professor, conducts much of his research in collaboration with the Departments of Anesthesiology and Surgery. Based on both laboratory studies and predictions suggested by the Harvard-MIT Broad Institute genomic data base, his lab is investigating the possible “repurposing” of the FDA-approved drug, phenoxybenzamine for treatment of a number of proliferative pathologic syndromes, including Complex Regional Pain Syndrome (CRPS), several human malignancies, and pulmonary arterial hypertension. This is based on the newly observed property of phenoxybenzamine to inhibit several histone deacetylase enzymes. The Broad Institute database also predicts significant anti-inflammatory, immunomodulatory activity for phenoxybenzamine; a study of the possible value of the drug to reduce the extent of permanent brain damage after traumatic brain injury (and stroke) is one area that is being pursued in relation to this property of the drug.
Daohong Lin, Ph.D., assistant professor, explores the regulation of inwardly-rectifying potassium channels (Kir) in epithelial cells. Both high potassium intake (HK) and sodium restriction stimulate aldosterone synthesis. However, HK stimulates renal K+ excretion and enhances natriuresis despite of high aldosterone whereas sodium restriction stimulates renal Na+absorption without increasing K+ excretion. The discriminated effects of aldosterone on K+excretion in response to hyperkalemia and volume depletion depend on the presence of Kir4.1 in the distal tubules. We apply molecular biological approaches and patch-clamp to identify the mechanisms by which K channels are controlled under dietary potassium/sodium condition, therefore examine the critical role of K secretion in modulating blood pressure.
Petra Rocic, Ph.D., associate professor, studies the cardiovascular complications of metabolic syndrome. Studies focus on the effects of transient, repetitive myocardial ischemia and myocardial infarction on short- and long-term cardiac and coronary artery remodeling, including arteriogenesis. The aim of these studies is to identify signaling pathways and cellular processes which limit myocardial damage caused by ischemia/reperfusion injury in normal animals and how they are altered in metabolic syndrome animals and human patients in order to develop treatment paradigms to prevent detrimental cardiac remodeling and left ventricular failure after myocardial infarction.
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.