Physiology and Pharmacology

Medical Students Summer Program 2012

 

 
 
MESSAGE FROM THE CHAIR:  Dr. Nader G. Abraham
    In my commitment to strengthen the academic and research environment, and to establish pre-eminence in biomedical research and strengthen our national and international presence, the faculty is encouraged to accept more medical students for summer research programs.  The department enjoys a climate of collegiality that goes beyond the boundaries of the department, as evidenced by significant cross-talk and collaboration with clinicians and other basic science departments. As a result, our medical students, residents and fellows perform joint research projects, especially in collaboration with cardiology, nephrology and orthopaedics. In 2011, we increased the number of medical students who presented their summer research by 25%. 
    We encourage medical students who are interested in research training to choose a lab (see below) as an elective in our department for this summer.  If you have minor training in a lab or experience in a lab, we will provide support for you.  
                                                                                                                                                    
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                                                            RESEARCH INTERESTS
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Dr. Abraham   

     Research programs in Dr. Nader Abraham’s laboratory are focused on vascular dysfunctions which are a prelude to cardiovascular and metabolic diseases including hypertension, stroke, diabetes and obesity, the role of oxidative stress, inflammatory cytokines, hypoadiponectinemia and lipid-derived from arachidonic acid in the initiation of vascular dysfunction. The central hypothesis focuses on heme oxygenase (the most potent anti-oxidant gene in the human body)-adiponectin-EET that plays an essential role in vascular function. We believe that heme oxygenase acts as a molecular "switch" to genetically reprogram the vascular endothelium through activation of a unique signaling cascade with amplification of protective circuits to provide resistance to vascular dysfunction. Heme oxygenase also serves as the mediator of cross-talk between adipose tissue and the vasculature.  Studies in his lab focus on the impact of adipocyte dysfunction on vascular endothelial integrity through the prism of heme oxygenase.
     Human biological materials and experimental animal models of diabetes and obesity are used to examine the use of molecular, gene therapy and stem cell interventions that amplify the heme oxygenase system. Additionally, one of our research approaches represents a powerful tool to identify therapeutic strategies and novel biomarkers for cardiovascular and metabolic diseases (e.g. circulating endothelial cells and progenitor stem cells [EPCs] for better prognosis).  We believe that the effect of anti-diabetic drugs alone or in combination with the antioxidant genes, have a differential impact on stem cell function and vascular diseases as well as on stem cells differentiation into adipocytes and osteoblasts.  The genomic approach and gene array analysis described in these studies represents a powerful tool to systematically investigate therapeutic approaches, and hence, facilitate translational research in hypertension, diabetes and the metabolic syndrome.  Additionally, the lab is developing genetic testing for several human genetic diseases to predict future pathophysiological conditions using cell therapy for disease prevention.

 

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 Dr. Jennifer Hill  

     My laboratory’s interests lie in understanding hypothalamic homeostatic mechanisms controlling body weight and fertility and the interactions between these two systems. The brain blocks reproduction in animals under metabolic stress. Within the hypothalamus, energy deficits suppress gonadotropin-releasing hormone (GnRH) release from a sub-population of neurons that maintain fertility. Anorexia, cachexia, and excessive exercise suppress reproductive cyclicity in humans and with it the estrogen release essential for bone health. Fully 5% of women of reproductive age suffer from infertility related to eating disorders. Furthermore, the incidence of exercise-related anovulation may reach as high as 61% in gymnasts and 78% in runners. On the opposite end of the spectrum, obesity and diabetes also negatively affect fertility. As rates of these diseases rise, it is urgent that we unravel the hypothalamic homeostatic mechanisms controlling body weight and fertility and the interactions between these two systems.
    The hypothesis underlying my research is that circulating metabolic factors (such as leptin, insulin, ghrelin, glucose, LC-FAs or PYY3-36) are perceived directly or indirectly by GnRH neurons of the hypothalamus and convey information that prevents GnRH release during a state of negative energy balance. Determining the mechanisms behind this metabolic-reproductive connection will provide much needed targets for medical treatment. The cornerstone of my laboratory’s efforts is timed, targeted genetic manipulation using the power of tissue-specific gene deletion. Combined with anatomical, electrophysiological, and physiological techniques this approach offers a powerful tool for investigating the hypothalamic control of metabolism and fertility.

 

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     Dr. Sudhir Jain 

Transcriptional regulation of genes associated with Human Hypertension

     My current research interest is to understand molecular mechanisms involved in hypertension and hypertrophy with special emphasis on the role of the renin-angiotensin system (RAS) which plays an important role in the regulation of blood pressure.  The Octapeptide Angiotensin-II is one of the most potent vaso-active substances known and is synthesized from its precursor molecule, antiotensinogen, which is primarily synthesized in the liver and to a lesser extent, in the kidney, brain, heart, adrenal, fat and vascularwalls by the combined proteolytic action of renin and angiotensin converting enzyme.  Recent studies have shown that patients with essential hypertension have higher plasma angiotensinogen levels and linkage studies have confirmed a direct relationship between angiotensinogen gene and essential hypertension.  However, molecular mechanisms involved in this process are not known.  In addition, molecular mechanisms involved in tissue and hormone specific expression of this gene remain to be identified.  In order to understand the mechanisms involved in its transcriptional regulation, we have constructed expression vectors where different deletions in the 5'-flanking sequence of the human angiotensinogen gene (5' untranslated region containing the promoter) are fused to the reported luciferase gene. Transient transfection of these expression vectors, combined with DNAase footprinting and gel mobility shift assay, have identified cis-acting DNA elements that are involved in the regulation of angiotensinogen gene expression in the cell lines from liver, brain, kidney and adipocytes.  The human angiotensinogen gene contains various polymorphic sites (SNP) in its promoter.  We have analyzed SNPs at -6, -20, -217, -532, -777, -793, -1074, -1564, -1565, -1679 positions in human AGT gene promoter.  We have identified transcription factors that bind to these sites.  Our hypothesis is that increased expression of the angiotensinogen gene as a result of differential binding of the identified transcription factors with these polymorphic sites may result in increased blood pressure in these patients.  We are now using transgenic animals containing the human angiotensinogen gene with different polymorphic sites to study the role of these polymorphisms in an in-vivo situation.

 

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     Dr. Bina Joe

    The Program in Physiological Genomics of the Department of Physiology and Pharmacology is focused on understanding the genetic components of pathophysiological condition of the cardiovascular, renal and autoimmune. systems.  The most prominent of all complex traits investigated in the Joe laboratory is blood pressure regulation.  Rat models serve as valuable alternatives to human studies for the identification and characterization of genetic factors/genes.  The main strategy is to identify the disease causative genetic factor/gene based on its location on the rat genome by linkage analysis and substitution mapping and/or gene expression and protein expression profiling using whole genome systems biology approaches.  We have identified at least 16 different genomic regions that harbor quantitative trait loci (QTLs) for hypertension in rats and successfully mapped several of these regions to unparalleled resolution of a few kilobases.  Positional cloning projects have progressed to the identification of multiple novel genes as prominent BP QTLs in rats.  Methodical mechanistic studies spanning from molecular to whole-organism physiology/pathophysiology are underway to determine the functional significance of the novel BP QTLs identified.  Genetic-engineering technologies such as the application of zinc-finger nuclease-based targeted gene disruption for creation of 'knock-out' and 'knock-in' rat models are also strategies integrated into our research for validation of the positionally cloned causal genetic biomarkers of blood pressure regulation.  Finally, the translational significance of our work is exemplified by the validation of the positionally cloned rat genes as being associated or linked with human hypertension. 

 

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Dr. Dong Hyun Kim


•  Adult Stem Cells from Human Bone Marrow, Cord Blood, Fat tissues and other tissues.
•  Mesenchymal Stem Cells (MSCs) and Hematopoietic Stem Cells (HSCs) for therapeutic resources.
•  Adipogenesis of MSCs from human bone marrow.

   The laboratory is focused on vascular dysfunction which is a prelude to cardiovascular and metabolic diseases including hypertension, stroke, diabetes and obesity, the role of oxidative stress, inflammatory cytokines, hypoadiponectinemia and lipid-derived from arachidonic acid in the initiation of vascular dysfunction. The central hypothesis focuses on heme oxygenase (the most potent anti-oxidant gene in human body)-adiponectin-EET plays an essential role in vascular function. We believe that heme oxygenase acts as a molecular "switch" to genetically reprogram the vascular endothelium through activation of a unique signaling cascade with amplification of protective circuits to provide resistance to vascular dysfunction. Heme oxygenase also serves as the mediator of cross-talk between adipose tissue and the vasculature.  Studies in this lab focuses on the impact of adipocyte dysfunction on vascular endothelial integrity through the prism of heme oxygenase and stem cell applications.

 

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   Dr. Ashok Kumar

    Research interests include molecular genetics of hypertension, role of single nucleotide polymorphisms (SNPs) in human essential hypertension and pregnancy induced hypertension.  

 

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 Dr. Mensah-Osman  

     Dr. Edith Mensah-Osman's laboratory is investigating the perturbations in the signaling pathways, which are involved in the mechanisms of obesity, fatty liver disease and diabetes.  The laboratory is also investigating the pathways linking metabolic disorders with osteosarcoma, an aggressive malignancy of the bone, to determine its role in tumor progression and drug resistance. 

 

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  Dr. Sonia Najjar

 Dr. Sonia Najjar’s research focuses on identifying the genetic and environmental interactions underlying obesity, type 2 diabetes and their cardiovascular complications.

     The laboratory pioneered the finding that CEACAM1 plays a key role in regulating insulin action by promoting insulin clearance in liver. By generating mouse models of loss- or gain-of function of this protein, the Najjar team observed that genetic inactivation/deletion of this protein causes insulin resistance, obesity and fatty liver disease, in addition to predisposing to type 2 diabetes and Non-alcoholic steatohepatitis (NASH) in response to high-fat diet. Current studies focus on the role of CEACAM1 in the pathogenesis of atherosclerosis and common types of cancer.

     The Najjar laboratory also investigates the central role of CEACAM2 proteins in insulin secretion and energy balance.

 

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   Dr. Nitin Puri  

     The endothelium is a major source of eicosanoids in blood vessels producing an important vasodilator, EET, generated by the cytochrome P450 system. HO-1 expression plays a significant role in regulation of the levels of eicosanoid metabolism and the ratio of  vasoconstrictors to vasodilators including Epoxyeicosatrienoic acids (EETs).  EET is also released by shear stress and methacholine. this release is inhibited by H202. Smooth muscle cells do not synthesize EET. Epoxidation of AA to EETs is catalyzed by a number of CYP isoforms that demonstrate tissue-specific expression and relative regioselectivity and stereospecificity. Members of the CYP2C and CYP2J are the predominant epoxygenases in liver, kidney, brain and blood vessels of rodents and humans. The pathophysiological significance of EETs and DiHETrEs stem from numerous studies describing potent stereospecific biological effects including vasodilation (acting as EDHFs), stimulation of ion transport, inhibition of inflammatory response and stimulation of epithelial cell growth. Studies showing that upregulation of EET levels or inhibition of the soluble epoxide hydrolase (sEH) provide protection against Ang II-induced renal injury, and that mice lacking sEH have lower blood pressure than wild-type control mice, further endorse EETs as crucial in limiting vascular disease.

     We hypothesize that HO-1 and EET are organized hierarchically and are inextricably linked forming a functionally-inter-related module in which HO-1 and EET work in concert to activate key protective systems, including adiponectin and downstream signaling molecules (AKT, AMPK), rendering the vascular endothelium resistant to injurious stimuli; consequently, a deficiency in one of these protective systems contributes to the manifestation of vascular injury in obesity. The goal of medical summer students will be to prove these objectives by:

•  Determining the consequences of long-term/permanent expression of HO-1 (HO-1 TG), using lentiviral gene transfer strategy, on vascular  function in response to a high fat diet and to establish the quantitative relationship between HO-1 expression, EET levels,  EC-SOD and   adiponectin.

•  Deciphering the interactions between HO-1 and EET and the role of adiponectin and EC-SOD in supporting HO-1-EET vascular protection.    We will determine whether deletion of HO-1 abrogates the vascular dysfunction-sparing effect of EET-agonist treatment.  This will involve both  a loss-of-function (HO-1 -/-, HO-1 +/-, HO-2 -/-) and a gain-of-function using lentiviral-mediated HO-1 gene transfer strategy.  We will further examine whether amplification of HO-1 or EET provides vascular protection in EC-SOD and adiponectin KO mice.

•  Determining whether permanent endothelial-specific (Cyp2J2 under the control of the Tie promoter) expression of EET (EET TG mice)       provides vascular protection and whether HO-1 expression is obligatory for the EET-mediated vascular resistance to oxidative stress in       animals fed a high fat diet.

•  Constructing and characterizing a mouse model that permanently expresses HO-1 in an endothelial cell-specific manner  (Lenti-VECAD-HO-1-TG) and transgenic mice (VECAD-HO-1 TG mice), and to determine the mechanism of vascular protection in mice fed a high fat diet.

    Our inability to understand vascular dysfunction limits our ability to develop proper treatment and is a major obstacle to improvement in the prognosis of vascular disease.  Findings from this proposal should provide seminal information on how the HO-1-EET axis influences the control of the vascular phenotype that is responsible for vascular protection as well as the framework for translational clinical research to both treat and prevent vascular disease that results from endothelial dysfunction.

 

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    Dr. Vazquez   
     Research in Dr. Guillermo Vazquez’s lab is focused on the role of non-selective cation channels, such as Transient Receptor Potential Canonical (TRPC) channels and nicotinic acetylcholine receptors, in molecular and cellular events of atherosclerosis. Atherosclerosis is a disease of the arterial wall with a dominant and maladaptive inflammatory response, and represents the leading cause of death in western societies, remaining as the main vascular complication of metabolic diseases such as diabetes, obesity and metabolic syndrome. Our group has recently discovered that endothelial TRPC3 channels are an obligatory component of the signaling underlying regulated expression of cell adhesion molecules and macrophage recruitment to endothelium, two critical events throughout all stages of atherosclerotic lesion development. We have also discovered a novel nicotinic acetylcholine receptor-dependent survival pathway in coronary endothelium. More recently, our lab has shown that TRPC3, through a mechanism not yet defined, is critical for macrophage survival and efferocytosis. To study this, our lab makes use of in vitro (primary and immortalized cell lines) and in vivo (global and conditional transgenic and knockout mice; bone marrow transplantation) models of endothelial and macrophage dysfunction, and a number of techniques (including patch-clamp electrophysiology, real-time camera-based fluorescence imaging, real-time amperometry, protein chemistry/molecular biology, morphometric and immunohistochemical analysis of atherosclerotic lesions in mice).  
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  • Molecular mechanism of membrane transported-mediated signal transduction.
  • Development of novel agonists and antagonists of receptor Na+/K+-ATPase.
  • Renal and cardiac physiology of endogenous cardiotonic steroids.

 

       Dr. Zi-Jian Xie        
Last Updated: 6/26/15