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, heart and 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
Nader G. Abraham, Ph.D., Dr. H.C., FAHA, professor, 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 effect of reprogramming white fat to brown stem cell with distal effect on heart (left ventricle function) function and signaling mechanism underlying the biological response obtained in human epicardial fat of obese and none-obese subjects during bypass. 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 illnesses.
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= 7874, 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. Recently our laboratory has demonstrated that the oral administration of A. muciniphila modulated the innate immune response observed an experimental periodontal disease. A novel mechanism implicated in the modulation of the pathogenic oral microbiome was recently identified. A. muciniphila’s beneficial oral administration in experimental periodontal disease was demonstrated recently.
Ercument Dirice, Ph.D., assistant professor. The Dirice Lab. is currently investigating mechanisms that regulate pancreatic beta cell survival and their resistance to stress-mediated apoptosis. More specifically, we are focused on beta cell heterogeneity to test the hypothesis that “Some β-cells display a variable capacity to survive and either “hide” or “escape” and/or are resistant to autoimmune mediated cell death”. Specific beta cell subpopulations which facilitate specialized tasks to adapt and/or protect themselves during different physiologic and pathophysiologic conditions have the potential to be harnessed to develop novel therapeutic approaches that protect β-cell loss, which is a common phenomenon in both type 1 and type 2 diabetes. Through the use of transgenic mouse models and both surgical and molecular techniques, the Dirice Lab identifies and investigates genetic, physiological, and chemical-mediated mechanisms of bolstering the survivability of beta cells when faced with immunologic attack or stress related apoptosis, as is distinctively harmful in diabetic patients. The lab currently focuses on evaluating the top candidates from previous analyses and research both in vivo and in vitro to find the translational relevancy of promising avenues to take advantage of in the beta cell genome.
Nicholas R. Ferreri, Ph.D., professor. Hypertension affects greater than 40% of the population in the United States and is an important risk factor for the development of heart disease, stroke, and kidney disease. Many hypertensive patients, especially African Americans, exhibit sensitivity to salt. Exaggerated stimulation of ion transporters in the kidney of these individuals increases the retention of salt, which heightens elevations in blood pressure associated with an increase in dietary salt intake. We are studying the effects of tumor necrosis factor-alpha (TNF), produced within the kidney, on adaptive mechanisms that control sodium chloride reabsorption and blood pressure homeostasis. We have developed precision molecular and genetic strategies that allow us to target TNF in specific renal and inflammatory cell types and expect our studies will 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, inflammatory neutrophil, and its underlying molecular and cellular mechanisms.
Sachin Gupte, M.D., Ph.D., 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.
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.
Nadler, Jerry L., M.D., adjunct professor, conducts research related to understanding the mechanisms leading to inflammatory damage to pancreatic beta cells as well as the cardiovascular complications of diabetes and obesity. Our work focuses on lipid mediators and transcription factors that also influence the immune system. In particular our funded projects from the NIH involve targeting 12-Lipoxygenase as well as STAT4. We have developed and are studying new small molecule inhibitors as potential therapeutics for diabetes treatment and prevention. We are also initiating new research to better understand the links between diabetes and COVID-19.
Michal L. Schwartzman, Ph.D., professor and chair, conducts research aimed at identifying the role of lipid autacoids in the regulation of inflammation and vascular function, and determining their contribution to the pathogenesis of hypertension and cardiovascular, renal and metabolic diseases. Our laboratory was the first to characterize a lipid molecule, namely 20-HETE, as a potent vasoactive and inflammatory mediator whose circulating levels are greatly elevated in hypertensive and obese subjects and in animal models of hypertension and obesity. Studies are aimed at understanding 20-HETE cellular and molecular mechanisms of action with the goal of uncovering novel therapeutic targets for the treatment of cardiometabolic diseases. The experimental approach is multi-faceted and includes the use of transgenic mice and genetically modified rats as well as molecular and pharmacological probes together with cell culture models.
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.
Charles T. Stier, Jr., Ph.D., associate professor, has conducted studies primarily in stroke-prone spontaneously hypertensive rats to elucidate the hormonal and cellular mechanisms that contribute to blood vessel damage. This work has led to the discovery that salt-induced kidney damage and stroke in these rats can be prevented by drugs or interventions that inhibit either the formation or the action of not only angiotensin II but the steroid hormone aldosterone as well.
Mario A. Inchiosa, Jr., Ph.D., professor emeritus, 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.