Program Director and Training Faculty
Program Director and Training Faculty
Dr. Katya Ravid (ravid@biochem.bumc.bu.edu), Professor of Biochemistry and Medicine and an Established Investigator with the American Heart Association, serves as the Program Director. Dr. Ravid has taught graduate courses including, Mechanisms of Cardiovascular Diseases, Basic Biochemistry / Molecular Biology and Gene Targeting (with emphasis on Cardiovascular Disease). Among other related experience, she has served as a Chairperson of the M.D./Ph.D. committee at the Department of Biochemistry, as a member of the Student Affair Committee, and has trained in her own lab several predoctoral and postdoctoral trainees. Dr. Ravid and the training faculty are highly committed to mentoring students during their research experience. Training faculty members, including Dr. Ravid, have been recognized by students at BUSM as “Special Educator” (in competing for Educator of the Year Award).
Description of the Research Activities of the Participating Faculty
Dr. Christopher Akey’s (cakey@bu.edu) research involves the use of structural electron microscopy and X-ray crystallography to study the function of protein translocation channels (Ribosome-ER channel, Nuclear Pore complex) and chaperones that assemble the Nucleosome, Apoptosome and snRNPs, with a focus on these properties also in smooth muscle cells.
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Dr. David Atkinson’s (atkinson@bu.edu) research focuses on molecular details of the structure, stability and dynamic properties of the plasma lipoproteins and their constituent apolipoproteins, particularly high density (HDL) and low density (LDL) lipoprotein. This information is vital to an understanding of the lipid interactions, apoprotein exchanges, lipoprotein cell surface interactions, receptor-mediated lipoprotein uptake, and lipoprotein inter-conversions that form the basis of lipid transport and metabolism. The conformational adaptability of the exchangeable apoproteins such as apoA-I, the major protein of HDL, is essential to both their structural role in lipoprotein stabilization and their functional roles as cofactors for enzymes, ligands for receptors, or mediators of reverse cholesterol transport. The precise molecular mechanism of this unique structural adaptability is the focus of a major component of research. A second focus concerns the analysis of the organization of apo-B and the localization of structural and functional domains on the LDL particle, using a combination of site-specific immuno-nanogold labeling and direct visualization of the bound LDL receptor.
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Dr. Victoria M. Bolotina’s (bolotina@bu.edu) research program is in ion channel regulation of vascular smooth muscle. Dr. Bolotina has steadily contributed to our understanding the mechanisms of activation of non-selective ion channels responsible for control of membrane potential and intracellular calcium and identification of calmodulin regulated iPLA2 as an intrinsic regulator of these ion channels.
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Dr. Richard Cohen’s (racohen@bu.edu) research programs of the Vascular Biology Unit are highly interdependent, and involve 1) basic mechanisms of calcium regulation in vascular smooth muscle, 2) mechanisms by which nitric oxide regulates smooth muscle contractility and signaling, 3) oxidant mediators such as NADPH oxidase and their role in mediating vascular remodeling and atherosclerosis in diseased arteries, 4) oxidant stress initiated by metabolic factors in diabetic vascular disease, 5) oxidant regulation by glucose-6-phosphate dehydrogenase, 6) post-translational modification of proteins by oxidants including nitric oxide and peroxynitrite in proteins such as endothelial NOS, prostacyclin synthase, sarcoplasmic reticulum calcium ATPase, p21ras, and manganese SOD. The current overarching theme of these projects is to understand mechanisms of cardiovascular disease by studying reversible and irreversible oxidant-mediated, post-translational protein modifications. Major methodologies utilized include molecular and cell biology, protein chemistry, proteomics, and microscopic imaging.
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Dr. Wilson S. Colucci’s (wcolucci@bu.edu) research goal is to understand the signaling mechanisms that mediate the development of myocardial remodeling and failure. Work is performed both in vitro in cardiac myocytes or in vivo in mouse and rat models of myocardial remodeling. The major scientific focus is on signaling molecules that regulate cardiac myocyte phenotype, and in particular, the role of reactive oxygen and nitrogen species in the regulation of myocyte growth, apoptosis and function. Studies are underway to elucidate both the sources of and targets for reactive oxygen species in the myocardium.
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Dr. Barbara Corkey’s (bcorkey@bu.edu) research interest is Metabolic Regulation of Signal Transduction in Pancreatic islets and Adipose Tissue. The main goal of work in the Corkey laboratory is to determine how fuels generate the signals to modulate exocytosis, electrical activity, metabolism and gene expression. It involves assessment of the influence of metabolites on intracellular signal transduction in adipocytes and pancreatic ß-cells. Recent emphasis has been on intracellular ion handling, respiration, the signaling consequences of cellular energy state, the influence of fatty acids on protein kinases and the role of fatty acids and long acyl CoA on signal transduction. Work is done in collaboration with scientists at Boston University School of Medicine, the Karolinska Institute, the Universities of Montreal and Chicago.
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Dr. Catherine Costello’s (cecmsms@bu.edu) research interest is in protein structure variations in cardiovascular and amyloid diseases. Research develops and applies new analytical methodologies, based primarily on mass spectrometry, for structural determinations of proteins, carbohydrates and glycoconjugates, in order to probe the processes underlying development, disease, immune system responses and aging. Two central areas of focus are oxidative stress in cardiovascular disease and the systemic amyloidoses, which often have cardiac system involvement as a major feature.
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Dr. Harrison Farber’s (hfarber@bu.edu) research focuses on endothelial cell biology, in particular, the response of the pulmonary vasculature to injury. He has extensive government and private funding and is an NIH-funded Principle Investigator on several grants. He is a member of several research groups both within the Pulmonary Center and in other divisions within the Department of Medicine: the Pulmonary Vascular Biology Group (Pulmonary Center); the Center for Excellence in Sickle Cell Disease (Hematology), the Scleroderma Vascular Disease Group (Rheumatology) and Pulmonary Vascular/Left Ventricular Study Group (Cardiology). Dr. Farber’s laboratory is investigating the response of the pulmonary vasculature in different etiologies of pulmonary hypertension using genomic and proteomic approaches to identify unique molecules as potential targets for new therapies for pulmonary hypertension associated with sickle cell disease, with scleroderma, and with left ventricular diastolic dysfunction.
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Dr. Lindsay Farrer’s (farrer@bu.edu) research focuses on identifying the genetic basis of several complex diseases. He is also developing genetic mapping methods for locating modifiers for disorders whose primary defects are already known, but account for only a small portion of the phenotypic variation. Such modifier genes will probably be more amenable than the primary structural genes to strategies for delaying or modulating expression. Working together with other BU researchers, Dr. Farrer’s lab is leading efforts to identify genes for hypertension. In collaboration with researchers at other academic institutions, Dr. Farrer’s lab is conducting genome scans to uncover genes conveying susceptibility to substance dependence and macular degeneration. In 2005, they identified a functional genetic variant in the complement factor H gene which accounts for approximately 50% of the attributable risk for macular degeneration, the leading cause of progressive vision loss and blindness in the elderly. Dr. Farrer’s group has also shown that the ?4 variant of apolipoprotein E (APOE), the strongest AD risk factor identified thus far, is more weakly associated with disease in men and persons older than 75 years. The aim of the currently funded project is to compare variations in genes related to vascular functioning with disease risk and pre-clinical changes evident on MRI scan of the brain in 1000 White, African and Asian American AD families.
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Dr. David Chui (David.Chui@bmc.org) concentrated on the study of hemoglobin ontogeny in mice and in man. He discovered that human embryonic hemoglobins persist throughout intrauterine life, and even into adulthood in some hereditary disorders. IN the context of this training program, he focuses on vascular complications associated with ß-thalassemia. Since joining the Boston University in 2003, Dr. Chui has established another successful Hemoglobin Diagnostic Reference Laboratory, to which patients’ samples have been referred from throughout Massachusetts, the United States, and beyond. It is a repository for unusual or novel globin gene mutations, some of which form the basis for further laboratory research. Dr. Chui continues to pursue issues related to thalassemia and population health. Concurrently, Dr. Chui is engaged in a large genetic association research project using SNP genotyping in β-thalassemia patients and their family members to search for hereditary factors that regulate Hb F production.
Dr. Jane Freedman’s (freedmaj@bu.edu) research interests focus on molecular regulation of pathways contributing to thrombosis and vascular disease, and their contribution to acute coronary syndromes. Coronary artery plaque rupture leads to platelet-dependent thrombosis and myocardial infarction. The major research initiatives in our laboratory include an emphasis in the molecular regulation of pathways contributing to thrombosis, vascular disease, and how these factors contribute to acute coronary syndromes. The main topics include: platelet signaling pathways, molecular regulation of platelet nitric oxide and reactive oxygen species, and the role of inflammation in thrombosis.
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Dr. Noyan Gokce’s (gokce@bu.edu) research examines the link between vascular endothelial dysfunction and clinical cardiovascular events. Dr. Gokce is a past recipient of a NIH Individual National Service Award and an AHA New England Affiliate Award examining mechanisms of endothelial dysfunction. Dr. Gokce is a member of the AHA Young Clinician –Investigator Committee, a Fellow of the American College of Cardiology, and Fellow of the American Society of Echocardiography. Current research interests include investigating mechanisms of vascular dysfunction in patients with atherosclerosis and obesity.
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Dr. James Hamilton’s (jhamilt@bu.edu) research has a major focus in obesity and diabetes, as they relate to vascular pathology, and on molecular aspects of fatty acid binding interactions and transport in plasma, cell membranes, and the cytosol, using state-of-the art methods in structural and cell biology. The group is characterizing the interactions of fatty acids, bilirubin, and drugs with serum albumin by 13C NMR spectroscopy, and correlating NMR results with crystallographic data to achieve site-specific information. To study the mechanisms by which fatty acids cross the membrane barrier between the plasma and the cytosol, they are developing a combination of fluorescence probes to distinguish and quantify individual steps of fatty acid transport in membranes. The mechanism by which FA move across membranes has immediate and important implications for the treatment of diseases and targeting of pharmacological interventions to reduce accumulation of fat in cells. A second major project focuses on translational research in metabolic syndrome and obesity. The group is exploring the hypothesis that a unifying feature of metabolic syndrome is enhanced deposition of lipids throughout the body outside of the normal adipose stores. These inappropriate stores include hepatocellular triglyceride, perivascular and pericardial triglyceride, and atherosclerotic lipids (mainly cholesterol). MR imaging techniques are used to identify and quantify site-specific abnormalities in obese patients that include the above fat stores and changes in vascular stiffness.
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Dr. Kastya Kandror’s (kkandror@bu.edu) research focuses on Diabetes, which represents one of the major health threats to modern civilization, and its worldwide prevalence is increasing at an alarming rate. Its impact on vascular pathology is evident. In diabetes, insulin cannot not stimulate glucose entry into the cell as it does in normal individuals. As a result, extra glucose stays in the blood and causes multiple health problems. Since insulin-regulated glucose transport is the major molecular defect in diabetes, it represents the main focus of the lab.
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Dr. William Lehman’s (wlehman@bu.edu) research involves structural studies on the assembly and function of actin-containing thin filaments in muscle and non-muscle cells. The principal goal is to analyze and elucidate the mechanisms of thin filament-linked regulation of muscle contraction. To accomplish this goal, the group uses a combination of molecular biology, electron microscopy and image reconstruction to better understand the interactions and dynamics of protein components of isolated and reconstituted thin filaments. Studies on mutants are carried out to better understand abnormal filament function in cardiac disease processes. The laboratory confirmed the steric-blocking mechanism of muscle regulation by identifying the positions assumed by tropomyosin on actin in the presence and the absence of Ca2+ using cryo-electron microscopy and negative staining. They have demonstrated that on activation tropomyosin moves away from myosin cross-bridge binding sites on actin in two steps, one induced by Ca2+ binding to troponin and a second induced by the binding of myosin to actin. The laboratory is continuing the above-mentioned studies to obtain even greater resolution of the processes involved. At the same time, the group is investigating the structural organization of troponin on thin filaments and the changes it undergoes on binding of Ca2+. They are also engaged in studies on the structural interactions of other actin binding proteins including ?-actinin, caldesmon, calponin, cortactin, and native and mutant dystrophin, namely proteins that play important roles in the organization of the cytoskeleton in striated and smooth muscles and in non-muscle cells.
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Dr. Matthew Nugent’s (mnugent@bu.edu) research interest focuses on growth factors and proteoglycans in cardiovascular disease: the role of extracellular matrix and heparan sulfate proteoglycans in controlling growth factor-receptor interactions and cell proliferation. Specific interests include: the regulation of vascular smooth muscle and endothelial cell function by fibroblast growth factor 2 and vascular endothelial growth factor, storage and release of growth factors in the extracellular matrix of the lung. Developing delivery systems for the control of angiogenesis is also a focus of study.
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Dr. Paul Pilch’s (ppilch@bu.edu) research focuses on how the modern Western diet coupled with a sedentary lifestyle has led to an epidemic of obesity, a consequence of which is a dramatic rise in the incidence of type II diabetes, a malfunction in insulin-regulated metabolism. This diabetes is a known potentiator of vascular pathology. At the cellular level, type II diabetes is characterized by failure of insulin to act in liver, muscle and fat, processes which tend to fail as we age. The group studies aspects of insulin signaling and action in the latter two tissues. Insulin resistance in muscle (and fat) derives from the failure of insulin to activate the tissue-specific glucose transporter GLUT4. The activation mechanism for this process involves vesicle trafficking and protein targeting with regard to GLUT4 and the insulin receptor. Dr. Pilch’s group is characterizing the formation and protein content of GLUT4-containing vesicles. These studies involve both fat and muscle cells, and we are also studying the physiological role of cell surface (plasma membrane) microdomains called caveolae that are particularly abundant in these tissues. Dr. Pilch’s group also studies the mechanism(s) by exercise also regulates some of these same parameters independent of insulin. Understanding these pathways will help us to figure out how they are compromised in pathophysiological states such as diabetes.
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Dr. Katya Ravid’s (ravid@biochem.bumc.bu.edu) research is focused on two interrelated projects pertinent to the molecular processes involved in the development and function of platelets and their precursors and the function of vascular smooth muscle cells. The studies bear on the basic mechanisms associated with the development of vascular pathologies such as atherosclerosis. The cells of all blood lineages arise from pluripotent hematopoietic stem cells. The mechanisms that regulate lineage commitment and the subsequent steps of cellular maturation are poorly understood. In the megakaryocytic lineage, the early committed cells undergo a unique cell cycle (endomitosis) leading to the formation of polyploid cells prior to fragmenting into platelets. The lab’s goal has been to study the genetic and signaling factors that control megakaryocyte/platelet development in the bone marrow and the quality of platelets that fragment from megakaryocytes at different ploidy states. Studies include: isolation of genes encoding lineage-specific proteins that control ploidy and/or lineage determination; transcriptional studies; cyclin-dependent regulation of the megakaryocytic cell cycle and mechanisms of responsiveness to thrombopoitin, a factor known to augment platelet levels and to influence their activity. Dr. Ravid’s group also focuses on the role of vascular and bone marrow cells (progenitors and mature) adenosine receptor in vascular function and regeneration post injury.
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Dr. Neil Ruderman’s (nrude@bu.edu) research has examined the role of AMP-activated protein kinase in the pathogenesis of endothelial cell dysfunction such as might occur in diabetes, obesity or atherosclerosis. The group has shown that activation of AMPK by pharmacological or genetic means protects cultured human endothelial cells against the apoptosis, insulin resistance and the mitochondrial dysfunction and inflammation caused by high glucose or elevated concentrations of palmitate or TNF?. It was also shown that decreased AMPK activity caused by SiRNA or infection with a DN-AMPK-adenovirus potentiates the effects of TNF? on both DCH fluorescence (oxidative stress) and NF?B transactivation in these cells. Current research is examining the mechanism(s) by which some fatty acids (e.g., palmitate) cause these changes and others (e.g., oleate) inhibit them.
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Dr. Flora Sam’s (florasam@bu.edu) research is focused on studying the mechanisms that mediate myocardial remodeling and heart failure. A major focus is to understand the role of aldosterone (specifically the pro-inflammatory and pro-fibrotic effects) in mediating the myocyte phenotype in cardiac remodeling. The group studies these effects in vitro and in vivo using cultured cardiac myocytes and genetically-modified mice, to determine the relationship between the molecular/cellular events involved in cardiac remodeling and alterations in physiological function that can be assessed at the single myocyte and whole heart level in genetically-modified mice.
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Dr. Barbara Schreiber’s (schreibe@biochem.bumc.bu.edu) research efforts are directed at understanding the role of lipid metabolism on smooth muscle cell function in atherosclerosis. Despite the known association between hypercholesterolemia and atherosclerosis, little is known about the involvement of the cholesterol status of smooth muscle cells on their phenotypic expression. Using a model of cultured primary aortic smooth muscle cells, they previously showed that treatment with native ßVLDL induces intracellular lipid droplet formation and cholesteryl ester accumulation, decreases apolipoprotein E synthesis and induces smooth muscle cell proliferation. It was also shown that ßVLDL activates mitogen-activated protein kinase via a G protein-coupled receptor which transactivates the EGF receptor. Recent efforts have been aimed at studying the effect of acute phase serum amyloid A on smooth muscle cell lipid metabolism. It is known that the serum amyloid A proteins are up-regulated by inflammatory cytokines however function remains speculative. The group is currently exploring the molecular mechanism responsible for the ability of serum amyloid A to mobilize endogenous cellular cholesterol and traffic it to the endoplasmic reticulum.
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Dr. Donald Small’s (dmsmall@bu.edu) research interests cover the general area of the physical properties of fats and oils, detergents, lipids, proteins and lipid-protein interactions. Specific systems of interest include artificial membranes (bilayers), surfaces and cores of native lipoproteins, and recombinant lipoproteins using specific lipids and either native or genetically engineered apolipoproteins. A biophysical approach is used to probe disease processes such as athersclerosis, lipoproteinemias and gallstone formation. Recent work includes: (1) physical characterization of stereospecific lipids and fats, (2) the recombination of lipids with native or genetically engineered fragments of apolipoproteins to produce recombinant lipoproteins, (3) physical analysis of recombinant lipoprotein particles and (4) studies of the metabolism of recombinant lipoproteins in whole animals, perfused livers and cell cultures. The mechanisms of progression and regression of atherosclerosis are also being pursued. A wide variety of biophysical, biochemical and physiological methods are used to probe these problems.
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Dr. Barbara Smith’s (smith@biochem.bumc.bu.edu) research goal is to establish a better understanding of the mechanisms involved in the control of collagen gene expression associated with cardiovascular system, inflammation and fibrosis. Collagen is a family of connective tissue proteins that play a critical role in remodeling after injury. The response to injury in the cardiovascular system usually requires controlled changes in collagen synthesis often resulting in excess collagen deposition as in arteriosclerosis or cardiac hypertrophy. During inflammation the matrix synthesis is decreased which contributes to thrombosis. Dr. Smith’s laboratory has been examining both activation and repression of collagen transcription using molecular biology approaches. They have investigated transcription mediators that up regulate inflammatory response through activation of MHC II and repress collagen type I transcription.
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Dr. Joseph Vita’s (jvita@bu.edu) research focuses on endothelium-derived nitric oxide and impairment of endothelial function in atherosclerosis and associated disease states. At the present time, his primary focus is the importance of intracellular redox-state for endothelial nitric oxide bioactivity. Dr. Vita supervises an integrated program of research examining this issue in the coronary and forearm circulation of patients, and in animal models of atherosclerosis. The lab has also embarked on a study in the Framingham Heart Study population to determine the clinical relevance of endothelial dysfunction.
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Dr. Kenneth Walsh’s (kxwalsh@bu.edu) research focuses on the molecular events that control normal and pathological growth in cardiovascular tissues. In particular, the group is interested in the signaling pathways and transcriptional events that coordinate cell cycle activity, hypertrophy and apoptosis. On going studies also focus on the role of stem cells and progenitors in cardiac regeneration.
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Dr. Vassillis Zannis’ (vzannis@bu.edu) research focuses on two directions: (1) Apolipoprotein gene regulation in vivo using antisense and transgenic methodologies and adenovirus-mediated gene transfer. The project focuses on the role of hormone nuclear receptors and factors bound to the apoCIII enhancer on the transcriptional regulation of the apoA-I, apoCIII, and apoA-IV gene cluster. (2) Elucidation of the structure-function relationship of human apoA-I and apoE and their relevance to cardiovascular disease and Alzheimer’s disease respectively, using in vitro mutagenesis, transgenic and gene transfer methodologies. Pertinent questions are the role of apoA-I in the biogenesis and the functions of HDL, the role of apoE in cholesterol and triglyceride homeostasis in the circulation, the role of apoE in lipid homeostasis and the pathogenesis of vascular disease.
