Faculty and Staff
Nicholas W. Shworak, MD, PhD
The roles of glycans in cardiovascular disease.
Cardiovascular diseases are the leading cause of death and disability in the world. Two major causes of these diseases are blood clotting and inflammatory processes occurring at/within the blood vessel wall. Endothelial cells, which line blood vessels, utilize sugar polymers to regulate anti-coagulant and anti-inflammatory pathways that stave off disease; however, the involved mechanisms and molecules are largely unknown. My lab seeks to uncover these molecular events and to translate this knowledge into the creation of novel diagnostics and therapeutics to combat the devastating impact of cardiovascular diseases.
Much of our research focuses on HSAT+, a specific polysaccharide sequence that binds the plasma protein antithrombin (AT). Since the 1980's, it has been known that vascular endothelial cells express HSAT+, which is structurally similar to heparin, a pharmacologic anticoagulant. Based on analogy to heparin, HSAT+ has long been thought to act as a natural anti-coagulant of the blood vessel wall. Towards testing the validity of this assumption I purified, characterized and cloned the key rate limiting enzyme (3-OST-1) that generates HSAT+. My lab subsequently generated 3-OST-1 knockout mice, which revealed that normal levels of HSAT+ are not required for normal hemostasis. My group is now pursuing the paradigm shifting hypothesis that HSAT+ is an anti-inflammatory molecule that mediates an anti-inflammatory signaling activity of AT. As part of this process, we are using 3-OST-1 knockout mice to evaluate the protective role of HSAT+ in disease process such as septic shock and atherosclerosis. We are exploring the potentially utility of using mutant forms of antithrombin to treat such disorders. In addition we are evaluating if human mutations of these molecules relate to human cardiovascular disease.
Aniko Fejes-Toth, PhD
The major research interest of Dr. Náray-Fejes-Tóth is the cellular and molecular mechanisms by which steroid hormones regulate kidney function and blood pressure. One project in her laboratory focuses on the elucidation of mechanisms that confer aldosterone-selectivity to mineralocorticoid target tissues. This study is based on the observation that the mineralocorticoid receptor apparently cannot distinguish between aldosterone and endogenous glucocorticoids, the blood levels of which are ~1000-fold higher than those of aldosterone. Aldosterone-selectivity in target cells is conferred by an enzyme, 11β-hydroxysteroid dehydrogenase, which metabolizes glucocorticoids to a biologically inactive form, and thereby allows aldosterone to occupy its receptor. Dr. Náray-Fejes-Tóth's laboratory discovered a new form of this enzyme, which is specifically present in aldosterone-target cells. The laboratory cloned the cDNA of this novel enzyme and currently examines its intracellular localization and the regulation of its cell-specific expression. Recent studies proved that mutations in the gene of this enzyme causes a fatal disase in children, called apparent mineralocorticoid excess.
Another project deals with the identification of early-induced genes regulated by corticosteroid hormones. Although the regulatory effect of aldosterone on sodium homeostasis and thereby blood pressure has been known for decades, the exact molecular steps through which these effects are achieved are still unclear. The goal of this project is to identify and characterize those genes that mediate the biological effect of aldosterone on sodium transport. Both projects involve molecular biological techniques and functional studies.
Michael Liu, MD, M.Sc
Regulation and function of small G-protein Rho signaling pathways in the cardiovascular system. Recent studies have showed that Small GTPases are the major regulators of cardiovascular function such as the vascular tone, smooth muscle cell growth, and cardiac muscle growth, proliferation and contractility. More evidences have accumulated to indicate Rho protein activation as a common component for several cardiovascular diseases such as hypertension, coronary and cerebral vasospasm, atherosclerosis, and diabetes. We are interested in RhoA specific guanine-nucleotide-exchange factor (GEF)-Syx, which activates RhoA by catalyzing the exchange of GDP for GTP. Our focus has been to determine the function of Syx and its regulation in these cardiovascular diseases. Ongoing and future studies using in vitro and in vivo approaches will focus on the various roles of Syx in cardiovascular physiology and physiopathology. These studies may provide new therapeutic information for tissue specific interventions in cardiovascular diseases.
Eva Rzucidlo, MD
Intimal hyperplasia and restenosis of stents is like a cancer of the arteries. This is due to the plasticity of the vascular smooth muscle cell. Statins have been noted to have significant benefits for patients with cardiovascular disease. Clarifying how statins exert their beneficial effects on reducing cardiovascular events, as well as improving graft patency, may improve our understanding of which patients would benefit most from statin therapy and could also focus future pharmaceutical research on more specific effective treatments. We are investigating the effect of statins on the mTOR pathway, which we have shown to be an important regulator of VSMC phenotypic modulation. We are further looking at the effect of endothelial cell senescence on the healing of arteries after injury.
Yolanda Sanchez, PhD
Cells have evolved intricate signal transduction pathways that allow them to integrate internal and external signals in order to respond to specific cues during development and during stress. Molecules that originate from neighboring cells, tissues, and pathogens, can act over short and long distances to elicit a physiological response. Signaling pathways can also be triggered within the cell, as is the case when cells are placed under alert following DNA damage or when there is a problem with DNA replication. Such information is transmitted via protein-protein interactions and protein modifications and leads to the alteration of gene expression and other events that regulate cell division, DNA repair or cell death. My laboratory focuses on checkpoint signaling events triggered by DNA damage or replication interference. We are taking genetic, biochemical and cell biological approaches to study these signaling pathways. We are interested in dissecting signaling complexes involved in the response to lesions that are caused by DNA damaging agents or stalled replication forks and determining how specific protein-protein interactions and cellular location are regulated to transmit this information.
The pathways that we study are involved in both the etiology and treatment of cancer. Loss-of-function mutations in mammalian checkpoint genes compromise the response to DNA damage at the cellular level and at the level of the organism lead to a predisposition to cancer. In addition, cancer therapies frequently rely on drugs or agents that trigger genomic instability by taking advantage of the fact that cancer cells have defects in the response to DNA damage. Therefore, the checkpoint kinases have made attractive drug targets as therapeutic enhancers of genotoxic cancer drugs.
Genomic instability is not only a contributor to the malignant phenotype but it has been found to be an early event in pre-malignant lesions and subsequent to oncogenic transformation, including activating mutations in KRAS and deregulation of cyclins such as Cyclin E. One hypothesis from these findings is that the checkpoint pathways act as a barrier to malignant transformation by inducing senescence or apoptosis following oncogene-mediated DNA damage during DNA replication. If this were the case then systemic administration of checkpoint inhibitors to cancer patients could result in secondary malignancies. Until now, it has been difficult to model the Chk1 pathway to study its role in cancer development and to explore its suitability as a therapeutic target due to the fact that Chk1 is essential for mouse development. We have generated mice with a hypomorphic allele of Chk1. By establishing a model of oncogene-mediated carcinoma with a hypomorphic allele of Chk1, we are in a unique position to study the role of Chk1 in the early stages of cancer development.
Craig Tomlinson, PhD
We have several research projects ongoing in the laboratory with the common theme of using high-throughput genomics approaches to study gene/environment interactions in development and disease.
First, we are interested in the fetal basis of adult diseases. The primary objective of our work is to (1) correlate genome-wide methylation and global RNA expression profiles to identify those genes, signaling pathways, and developmental programs affected by an in utero toxicant exposure during development that leads to an adult disease, and (2) determine whether the epigenetic changes in the developmental programs are inherited.
A second interest in the lab is to characterize the role of the aryl hydrocarbon receptor (AHR) as a mediator in the response to environmental toxicants, e.g., arsenic. The AHR is also implicated in such key developmental roles as immune system maturation, extracellular matrix deposition and modeling, organogenesis, and vascularization.
A third project in the lab involves developing new genomic methods and approaches.
Follensbee, Joanie - Administrative Assistant
Kobayashi, Takashi, PhD - Research Associate
Shipman, Samantha - Research Technician
Smits, Nicole, PhD - Research Associate