Director: Professor Harold Singer
Co-Director: Professor Arif Asif
Under the leadership of Drs. Harold Singer and Arif Asif, the Center for Cardiovascular Sciences and the division of Nephrology & Hypertension at Albany Medical College have teamed up to create a Renal Translational Research Program with the goal of research, education and developing innovative therapeutic platforms to improve patient care. The program is focusing on various aspects of chronic kidney disease, hypertension and vascular access failure.
Dr. Asif is also the founding Program Director of Nephrology Fellowship Training Program at Albany Medical College. He is a national and an international figure in the area of Interventional Nephrology and is the Past President of the American Society of Diagnostic and Interventional Nephrology. He has published over 120 articles in high-impact peer-reviewed journals, chaired multiple scientific meetings and has delivered over 200 lectures at national and international scientific meetings. He has received multiple awards for teaching, research and scholarly activity and excellence in patient care. He serves as an editor, editorial board member and reviewer of numerous journals in NEJM, JAMA, KI, CJASN, AJKD and Seminars in Dialysis. He has conducted both industry and NIH funded studies. His current research is focusing on various aspects of dialysis access including novel therapeutic interventions to halt neointimal hyperplasia in fistulas, biomarker identification in hypertension, peripheral vascular disease in the dialysis population, surveillance of vascular access, acute kidney injury and hypercalcemia.
Harold A. Singer, Ph.D. earned his B.A. from SUNY Binghamton and Ph.D. from University of Virginia School of Medicine. He serves as the Professor and Director of Center for Cardiovascular Sciences. His research interests center on vascular smooth muscle (VSM) cell biology and function in the vascular remodeling response to injury and disease.
Vascular smooth muscle is the principal (by mass) cellular component of the blood vessel wall and in its quiescent differentiated state contracts and relaxes to adjust blood pressure and flow. Hypertrophic growth and proliferation of VSM contributes to chronic hypertension, a major risk factor for heart disease and stroke. VSM is not terminally differentiated and a characteristic property of this cell is reversible de-differentiation resulting in a “synthetic” phenotype that proliferates, migrates and produces extracellular matrix.
The transition from contractile to synthetic phenotypes is stimulated by environmental stimuli and growth factors produced in response to injury and disease and synthetic phenotype VSM is a key component of occlusive vascular proliferative diseases, including atherosclerosis. Thus, VSM is a potential therapeutic target for a number of vascular diseases, including hypertension and vascular access failure in hemodialysis patients.
Ca2+ is an essential intracellular second messenger in virtually all cells and participates in control of diverse cellular processes including muscle contraction, gene transcription, cell growth and motility. One ubiquitous but poorly understood mediator of Ca2+ signals is the multifunctional serine/threonine protein kinase, Ca2+/calmodulin-dependent protein kinase II (CaMKII). This laboratory has been instrumental in discovering isoforms of CaMKII that are variably expressed in all cells and tissues and we are engaged in understanding the relationship between the complexities of CaMKII structure and specific cellular functions. We have developed an extensive set of biochemical tools, imaging approaches (live cell, confocal immunofluorescence, and TIRF microscopy), molecular mutants, and most recently genetic mouse models to assess CaMKII function, particularly in VSM.
With these tools, are current research goals are to determine the function of CaMKII isoforms in regulating specific transcriptional pathways that lead to induction of a pro-inflammatory and proliferative VSM phenotype and determine mechanisms of localized CaMKII activation in specific subcellular compartments and function in VSM polarization and directional motility. In collaboration with Dr. Arif Asif, we will determine the contribution of signaling mediated by this protein kinase in the control of neointimal hyperplasia in animal models of vascular injury and arteriovenous fistula (AVF) failure and extrapolate these findings to AVF maturation and failure in humans.
David Jourd’heuil, Ph.D. is a Professor in the Center for Cardiovascular Sciences. He has made important contributions to the characterization of the chemical biology and signaling properties of the free radical nitric oxide (NO). His work has focused on the mechanisms of action of nitric oxide (NO), reactive oxygen and nitrogen species (ROS/RNS), and heme protein interactions. Elucidating these fundamental processes is key to understanding cardiovascular diseases such as atherosclerosis or vasculopathies including angioplasty restenosis or dialysis vascular access failure.
Nitric oxide (NO) is a small diatomic gaseous molecule generated by a family of enzyme termed nitric oxide synthase (NOS) and regulates many aspects of vascular physiology and pathophysiology. Although the means by which NO is produced and exert its effect have been characterized to some extent, the mechanism by which NO is cleared and its signaling turned-off in the vascular wall is poorly understood. To understand how the vessel wall inactivates NO, his team has focused on cytoglobin (CYGB), a new member of the globin vertebrate family with poor functional annotation.
This work has characterized the expression of CYGB in intact vessels and in vascular smooth muscle and demonstrated that CYGB contributes to NO inactivation in cell systems. Current studies are aimed at delineating the role of CYGB in regulating NO bioavailability during vascular injury and elucidating NO-independent functions of CYGB. His laboratory utilizes everything from animal models and isolated blood vessels, cell culture techniques and molecular biology, to biochemical and biophysical analysis for the study of free radicals and oxidants.
Professor Jourd'heuil has a keen interest in the development of neointimal hyperplasia in the settings of hemodialysis vascular access. Research in this area is directed towards antioxidant systems, and sources of ROS/RNS that include NADPH oxidase (NOX), Nitric Oxide Synthase (NOS), and mitochondrial derived oxidants. A primary focus is the role of hemoglobins including CYGB as an adaptive response to the neoplastic injury associated with hemodialysis vascular access. Mechanisms of actions explored include vasodilation, anti-apoptotic, and anti-inflammatory actions. He is working closely with the Division of Nephrology and Hypertension on various aspects vascular access failure and kidney disease.
Roman Ginnan, Ph.D. is an Associate Professor in the Center of Cardiovascular Sciences. His research interests focus on intracellular signaling networks that mediate G-protein receptor- and receptor tyrosine kinase- induced activation of vascular smooth muscle (VSM) cellular functions. Vascular pathologies including restenosis, vein graft intimal hyperplasia, and atherosclerosis are characterized by dramatic phenotypic changes in differentiated VSM cells, leading to increased VSM cell proliferation, migration, and apoptosis accompanied by a significant inflammatory response.
Secreted growth factors such as platelet- derived growth factor (PDGF) and pro-inflammatory cytokines such as Interleukin-1 (IL-1) are important determinants of the cellular functions associated with the progression of vascular diseases. PDGF and IL-1 exert their influence by initiating protein kinase-dependent phosphorylation events, facilitating protein-protein interactions, increasing intracellular levels of reactive oxygen species (ROS), and regulating gene transcription.
Our recent work has delineated significant roles for the multifunctional serine/threonine protein kinases, CaMKII and PKC, in mediating both PDGF- and IL-1-dependent cellular responses such as VSM cell proliferation and migration. These signaling pathways are networked with parallel pathways including Src-family tyrosine kinases, mitogen-activated protein kinases (MAP kinases) and oxidative signaling mediated by NADPH oxidases (NOX) 1 and 4 to control complex cellular responses leading to vascular wall remodeling in response to injury and disease.
One current goal is to understand the mechanisms and function of these complex signaling networks in arterialized vein remodeling and arteriovenous fistula failure in both mouse models and human samples.
The proper regulation of fluid and protein flux is critical for maintaining normal tissue function. This is accomplished by a number of transmembrane cell-cell adhesion proteins that, when coupled with their binding partners, contribute to the adhesion of one endothelial cell to another. The adherens junction complex, comprised of cadherins and the catenins, is a major adhesion structure that connects to the actin cytoskeleton. VE-cadherin is found specifically in the endothelial cell adherens junction and has been implicated in playing a fundamental role in controlling the transport across the endothelial barrier and in regulating angiogenesis.
The cytoplasmic domain of VE-cadherin binds to β-catenin and plakoglobin, both of which bind to α-catenin, a protein that supports the interaction of the VE-cadherin-catenin complex with the actin cytoskeleton. In addition to catenins, VE-cadherin has been found to interact with other signaling molecules and to serve as a scaffolding molecule that participates in a signaling network that controls endothelial cell-cell adhesion. The research in my laboratory has focused on studying the role of p120 catenin which binds to the juxtamembrane domain of VE-cadherin. Binding of p120 to the JMD region regulates the localization of VE-cadherin to the plasma membrane by inhibiting endocytosis of VE-cadherin.
Our research has demonstrated that p120 is critical to maintaining barrier function of the endothelial monolayer and that this is due in part to endocytosis. Ongoing research in the laboratory is trying to determine how p120 regulates endothelial function in addition to regulating endocytosis.
The laboratory is also interested in how Src Family Kinases play a role in regulating endothelial monolayer permeability. Activation of Src family kinases (SFK) and the subsequent phosphorylation of VE-cadherin have been proposed as major regulatory steps leading to increases in vascular permeability in response to inflammatory mediators and growth factors. Data from our laboratory has shown that Src-induced tyrosine phosphorylation of VE-cadherin is not sufficient to promote an increase in endothelial cell monolayer permeability and suggest that signaling leading to changes in vascular permeability in response to inflammatory mediators or growth factors may require VE-cadherin tyrosine phosphorylation concurrently with other signaling pathways to promote loss of barrier function. Ongoing research is being performed to determine how multiple signaling pathways work together to alter endothelial barrier function pathways. Endothelium plays a major role in the genesis of hypertension and serves as an important focal point for hypertension research.
Xiaochun Long, Ph.D. is an Assistant Professor in the Center for Cardiovascular Sciences whose major research interest is to understand the transcriptional networks that regulate vascular smooth muscle cell (VSMC) phenotype plasticity. VSMC phenotype plasticity and adaptation to environmental stimuli underlie VSMC proliferation, migration and extracellular matrix remodeling that contribute to the pathogenesis of such vascular diseases as atherosclerosis, restenosis, hypertension, vein graft failure, and transplant arteriopathy. Dr. Long uses molecular and genetic approaches, such as RNAseq and mouse transgenic models, to identify human VSMC-specific genes and regulatory factors and test their function in mouse models of vascular injury and disease.
Three specific research projects are to:
1.) Define the mechanisms underlying an unexpected negative function of a well-known mitogen-activated protein kinase (MAPK14) to regulate VSMC differentiation. In this role, signaling through MAPK14 regulates VSMC phenotype plasticity by promoting proliferation and migration and negatively regulating the differentiation program. We will test this mechanism using mice with VSMC-specific deletion of the MAPK14 gene and in the disease contexts of abdominal aortic aneurysm, and in collaboration with the Division of Nephrology, arterio-venous fistula failure.
2.) Define the function of novel long non-coding RNAs in VSMC phenotypic adaptation. Recently, papers released from the ENCyclopedia Of DNA Elements (ENCODE) NIH Consortium described more than 80,000 transcribed long non-coding RNAs (lncRNAs), a number far exceeding that of protein-coding genes, suggesting a dominant role in the mammalian genome. lncRNAs have been shown to function as important regulators in stem cell pluripotency, cellular differentiation, cell cycle progression and in human disease, but there is a paucity of information about lncRNAs in vascular pathobiology. Using RNAseq, we have discovered a subset of novel lncRNAs restricted to human VSMC and closely linked to VSMC adaptation.
Studies are underway to define the functionality of these potential lncRNAs in VSMC phenotypic adaptation by utilizing the established in vitro or ex vivo VSMC culture systems from human and mouse arteries and veins, as well as transgenic/knockout mouse models.3.) The aforementioned RNAseq data also uncovered a number of novel protein-coding genes which are potentially important in VSMC phenotypic adaptation. One of our major goals is to define the role of these novel protein coding targets in the vasculoproliferative response to carotid artery injury, abdominal aortic aneurysm, and arteriovenous fistula failure using both human specimens and mouse models.