Immunology and Vascular Biology Training Program

Summary of Faculty Research

Mentor Research Programs
(Click on a highlighted name to view the faculty's homepage)

Linda K. Curtiss, Ph.D., Professor, Department of Immunology and Microbial Science

Atherosclerosis is a chronic inflammatory state in large and medium sized arteries that can lead to acute cardiovascular events such as myocardial infarction and stroke. To identify the key cellular and molecular participants in this complex disease, Dr. Curtiss studies the pathogenesis of atherosclerosis in gene knockout mice that have chronic hyperlipidemia including low-density lipoprotein receptor-deficient mice. Both innate and acquired immune responses contribute to the vessel wall pathology of atherosclerosis. Multiple components of oxidized lipoproteins can activate cells of both the innate and acquired immune systems and influence disease outcome. The Toll Like Receptors (TLR), which are important in microbial disease and for their ability to initiate inflammatory responses, are major players in atherosclerosis. Dr. Curtiss has discovered that TLR2 expression on endothelial cells residing at sites of disturbed flow promotes atherosclerosis in response to endogenous agonist formed during hyperlipidemia. TLR2 activation promotes macrophage and lipid accumulation and activation of TLR2 on leukocytes by an exogenous agonist augments these events. The laboratory continues to study the participation of macrophage produced phospholipid transfer protein (PLTP) in atherosclerosis and of TLR signaling in the initiation and exacerbation of atherosclerosis.

Ann J. Feeney, Ph. D., Professor, Department of Immunology and Microbial Science

A main focus of Dr. Feeney is the molecular analysis of the epigenetic, genetic and transcriptional mechanisms in B cell development and the epigenetic regulation of germinal center B cell differentiation. Dr. Feeney has published several studies on the various influences of transcription factors such as Pax5, E2A and EBF on the process of V(D)J recombination and on B cell development. The laboratory is highly experienced in molecular approaches to study non-random gene utilization, epigenetics and antibody repertoires, including ChIP, ChIP-seq, and deep sequencing. 3D-FISH and chromosome conformation capture are being used to study the changes in the 3-dimensional structure of the IgG locus by transcription factors and by the CTCF/cohesin complex. A related issue is to determine what controls the changes in the epigenetic profile and in the 3-dimensional structure of the receptor loci at the developmental stage of rearrangement. 

Brunhilde Felding-Habermann, Ph.D., Associate Professor, Department of Molecular and Experimental Medicine

Dr. Felding-Habermann studies the molecular mechanisms of tumor cell metastasis with specific emphasis on the interactions of tumor cells with the host microenvironment, including the blood and vessel wall. Her current research is guided by the hypothesis that a population of aberrant stem-like cells within a breast tumor is critically involved in the initiation of metastatic disease, that these cells express constitutively activated adhesion receptors which promote tumor cell dissemination, and that these activated adhesion receptors are targets for the identification and inhibition of metastatic tumor cells. Metastatic breast cancer cells particularly adapt to the microenvironment of the brain and changes in highly metastatic cells revealed by proteomic and gene expression analysis provided clues for functional pathways that control metastatic activity. The laboratory applies broadly in vitro and in vivo approaches to identify inhibitory strategies for these pathways with significant translational impact.

Velia Fowler, Ph.D., Professor, Department of Cell Biology

Dr. Fowler’s research aims to elucidate how actin cytoskeleton architecture and dynamics contributes to normal cell and tissue physiology, and to the pathogenesis of human diseases in a variety of contexts.  We study three problems: 1) biogenesis of the biconcave, flexible red blood cell and its survival in the circulation, 2) structure and function of the long lens fiber cells that form the transparent and resilient eye lens, and 3) myofibril structure and contraction of striated muscle.  We focus on the tropomodulin (Tmod) family of actin pointed end capping proteins that were discovered in my laboratory.  Our studies with proteins, cultured cells, transgenic mice, and human tissues have shown that Tmods are critical for actin filament length and stability in the spectrin-actin scaffolding network on membranes, and in the thin filaments of striated muscle myofibrils.  For example, absence of Tmod1 in red blood cells leads to a disrupted spectrin-actin network resulting in anemia due to red blood cell membrane instability and shortened lifespan. In skeletal muscle, Tmods control precise thin filament lengths in myofibrils, determining muscle biomechanics and stabilizing sarcomere structure which is disrupted in hereditary muscle diseases such as nemaline myopathy.  Tmods also stabilize a novel -actin filament linking system essential for sarcoplasmic reticulum architecture, calcium handling and linkages to myofibrils, that is disrupted in muscular dystrophy.  The laboratory uses a broad spectrum of approaches, including in vitro protein binding and actin polymerization assays, confocal fluorescence microscopy and 3D image analysis, development and physiology of transgenic mouse models, and translational studies in human cells and tissues.

Philippe A. Gallay, Ph. D., Professor, Department of Immunology and Microbial Science

Dr. Gallay’s research focuses on the interplay between host factors and viruses, specifically two prime human threats – the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV). More than 33 million people are living with HIV and an estimated 170 million people worldwide are chronically infected with HCV and more than 350,000 people die from HCV-related liver diseases each year. In the absence of vaccine for both HIV and HCV, there is an urgent need to develop new antiviral therapies to treat people, who are already infected, or to develop new approaches to interrupt viral transmission. A main goal of the laboratory is to identify host factors critical for viral infection and to exploit them as targets for the development of novel antiviral therapies. Ongoing research is focused on syndecans, the microbicidal C5A peptide and a family of host factors, the cyclophilins, which are critical for both HIV and HCV replication. The current major goal of the laboratory is to understand the mechanisms of action of cyclophilin inhibitors in inhibiting viral replication.

John H. Griffin, Ph. D., Professor, Department of Molecular and Experimental Medicine

Dr. Griffin is involved in long-term studies of plasma proteins that regulate thrombosis and hemostasis. He discovered human hereditary protein C and protein S deficiencies and has continued to advance the field in basic biochemical studies of human protein C and protein S and clotting factors, clinical studies of these proteins, and preclinical animal injury models that have probed the pathology, physiology and pharmacology of activated protein C (APC) and protein S. His current research is focused on proof of principle studies of murine protein C and protein S and is centered on preclinical murine studies that may change our fundamental understanding about the mechanisms and receptors that mediate APC’s life-saving activities, about the in vivo activities of protein C and protein S, and about potentially novel therapeutic APC variants with superior activity profiles. His laboratory's interdisciplinary approach continues to define molecular mechanisms or defects that are related to the development of thrombosis and ischemic stroke, to elucidate the mechanism underlying the strong epidemiologic association between hyperlipidemia and hypercoagulability, and to engage fully in research that extends from bench to bedside.

Lindsey A. Miles, Ph. D., Associate Professor, Department of Cell Biology

Dr. Miles studies how interactions of proteolytic systems, specifically the plasminogen activation system, with cell surfaces modulate cellular function and how cells modulate protease systems via positive feedback mechanisms. Recently, using a proteomics approach and a monocyte progenitor cell line, Dr. Miles identified a novel protein, the plasminogen receptor, Plg-R_KT, which has unique properties including a transmembrane topology with a carboxyl terminal lysine exposed on the cell surface in an orientation to bind plasminogen and stimulate plasminogen activation and is colocalized with and physically associates with the urokinase type plasminogen activator receptor (uPAR). Ongoing research employs newly developed reagents including specific function-blocking anti-Plg-R_KT antibodies, region specific peptide mimetics,and Plg-R_KT protein expression systems to address the role of this new plasminogen receptor in inflammation and cancer progression.  

Laurent O. Mosnier, Ph. D., Assistant Professor, Department of Molecular and Experimental Medicine

Dr. Mosnier studies the biochemistry of the coagulation system and cell signaling of the cytoprotective protein C pathway. The goal of the research is to gain novel insights into the molecular mechanisms of cytoprotective actions mediated by the endothelial protein C receptor (EPCR) and to define the structure-function relationships for EPCR in the transduction of protease activated receptor-mediated cytoprotective signaling. The laboratory uses immunological, biochemical and genetic approaches to define cellular events and agonist biased signaling specificity of the anti-apoptotic endothelial cell signaling pathway.

David Nemazee, Ph. D., Professor, Department of Immunology and Microbial Science

Dr. Nemazee has a long standing research interest in B cell development, immune tolerance, and autoimmunity. Dr. Nemazee was among the first to take advantage of transgenic mouse technology to study immune tolerance, and has continued to use genetic engineering to facilitate in vivo analysis of immune tolerance. Among the accomplishments were the first in vivo demonstrations of B cell clonal deletion, receptor editing, and B cell peripheral tolerance to tissue antigen. Dr. Nemazee carried out mechanistic studies on the signaling pathways that regulate receptor editing, the role of BAFF in the immune system, and the roles of apoptotic pathways in tolerance. The recently developed antibody gene targeted mice that spontaneously develop cardiolipin antibodies have the potential to provide new insight into autoimmune mechanisms in cardiovascular disease.
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Glen R. Nemerow, Ph. D., Professor, Department of Immunology and Microbial Science

Human adenoviruses are a major cause of acute respiratory, intestinal and ocular infections. Dr. Nemerow’s research is focused on gaining a better understanding of adenovirus interactions with host cells and to investigate basic mechanisms involved in virus attachment, internalization, membrane penetration and nuclear localization. These studies focus on the signaling events initiated by cell integrins that promote adenovirus endocytosis. Fundamental knowledge gained from virus-host cell interaction studies is exploited for the design of novel viral vectors with increased capacity to deliver therapeutic genes to specific cell types including endothelial, vascular smooth muscle cells and photoreceptors. In particular, adenoviral vectors are being evaluated as delivery vehicles for cardiovascular diseases as they have a high degree of tropism for the heart. Dr. Nemerow is interested in designing optimized vectors that increase vascular cell tropism as well as avoid the adaptive and innate immune responses that can limit the efficacy and safety of adenovirus gene transfer..

Michael B. Oldstone, M. D., Professor, Department of Immunology and Microbial Science

Dr. Oldstone has been a major scientific contributor to the biology, immunology, virology, biochemistry, molecular and cell biology of persistent virus infections and their complications. Dr. Oldstone provided the initial insight of how viruses cause suppression of the immune system and persistence in the central nervous system, was the first to show that adoptive immunocytotherapy could cure a persistent infection, including infection of CNS cells, and has mapped out the mechanism and immune cells involved in this process. The laboratory studies host virus interactions during infections with HIV, measles and LCMV, an excellent model for viral hemorrhagic fevers.  Recently, the laboratory has begun to explore the role of sphingosine-1-phosphate (S1P) and drugs that act on S1P receptors as therapies for inflammatory diseases.

James Quigley, Ph. D., Professor, Department of Cell Biology

James Quigley, Ph. D., Professor, Department of Cell Biology
Dr. Quigley studies proteolytic enzymes that are functionally involved in distinct physiological and pathological processes. Two enzyme families presently under study include the matrix metallo proteases (e.g. MMP-9, MMP-1) and the serine proteases (e.g. uPA and plasmin). Dr. Quigley addresses the role of these enzymes in angiogenesis and the different steps of tumor metastasis using an in vivo model system in the developing chick embryo and immunological and proteomics approaches to identify new molecular determinants for tumors cell intravasation. The laboratory is currently interested in the contributions of leukocyte populations to tumor cell metastasis..

Wolfram Ruf, M. D., Professor, Department of Immunology and Microbial Science

Dr. Ruf is interested in coagulation proteases and their signaling mechanisms in thrombosis, inflammation, angiogenesis and cancer. The ongoing research is focused on the cellular control of tissue factor (TF) thrombogenic pathways by protein disulfide isomerase and inflammatory P2X7 signaling, the cell signaling of the coagulation pathways via protease activated receptors and integrins, and the regulation of myeloid cell inflammation by coagulation protease signaling. The laboratory studies the complex molecular interactions of the TF coagulation pathway in cellular and animal models with an interest to develop novel translational concepts in thrombosis research. New genetic mouse models of the protease activated receptor (PAR) 2 are under development to define relevant PAR2 activating proteases that contribute to cancer progression, inflammation, and obesity.
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Zaverio M. Ruggeri,  M. D., Professor, Department of Molecular and Experimental Medicine

Dr. Ruggeri studies the role of platelets in thrombosis and inflammation. His basic research interest is focused on the structure and function of von Willebrand Factor (VWF) and its platelet receptors, particularly the glycoprotein (GP) Ib-IX-V complex. His laboratory uses a variety of research tools including protein chemistry, structural biology, cell biology, molecular biology and genetics, real-time videomicroscopy and in vivo thrombosis models for the study of platelet and coagulation function ex vivo under controlled flow conditions as well in vivo in response to vascular injury. Dr. Ruggeri collaborates with experts in chemistry and bioengineering to establish novel diagnostic and therapeutic nanodevices specifically targeted to areas of vascular lesion with the goal to improve the diagnosis and treatment of cardiovascular diseases.

Linda Sherman, Ph. D., Professor, Department of Immunology and Microbial Science

Dr. Sherman studies the discrimination between self and non-self by the immune system. This function is crucial to eliminate foreign pathogens without harm to the tissues. Autoimmune disease represents aberrant immune destruction of self-tissue, whereas cancer is, in part, due to immune tolerance of self. The laboratory utilizes a variety of transgenic murine models in order to study autoimmunity and tumor immunity and applies unique assays to measure the various checkpoints of tolerance induction of T lymphocytes for genetic studies of type 1 diabetes.

Raymond Stevens, Ph. D., Professor, Department of Molecular Biology

Dr. Stevens has been at the forefront of high throughput methods in structural biology. This endeavor has included pioneering microliter expression/purification for structural studies, nanovolume crystallization, automated image collection, and robotics for collecting synchrotron beamline data. His laboratory is focused on membrane protein crystallization and has been interested in G protein-coupled receptor (GPCR) research since the early 1990’s. Starting with the crystal structures of the human β2-adrenergic receptor bound to the partial inverse agonist carazolol and timolol in 2007, the laboratory determined a series of structures of GPCR of great importance for cardiovascular medicine. These structures provide a high-resolution view of a human GPCR bound to diffusible or peptide ligands and include the human A2A adenosine receptor bound to various ligands, the human CXCR4 chemokine receptor bound to small molecule and cyclic peptide antagonists, the human D3 dopamine receptor bound to the antagonist eticlopride, the human histamine H1 receptor bound to the antagonist doxepin, the human sphingosine 1-phosphate receptor subtype 1, the human kappa opioid receptor and the human nociceptin receptor. The current research programs continue to focus on understanding structural diversity among members of the GPCR family, as well as technology development to understand mechanisms of signal transduction and coupling of GPCRs with their partners including G proteins, GPCR kinases, and arrestin.

Charles Surh, Ph. D., Professor, Department of Immunology and Microbial Science

Dr. Surh is interested in defining the factors that regulate survival and homeostasis of various populations of mature T cells under physiological conditions. Although one of the main purposes of the immune system is to eliminate foreign antigens, it co-exists peacefully with immense amounts of foreign antigens originating from the commensal microflora, food and innocuous environmental antigens that reside at or enter the mucosal tissues. How such a truce is established between the immune system and the commensal antigens is largely unclear. The laboratory is interested in defining the role of T cells in establishing the tolerance to commensal antigens. In addition, since the homeostatic cytokines are essential for survival, expansion and effector function of nearly all populations of T cells, the laboratory is also interested in exploring their therapeutic potentials for modulating T cell populations in cancer or autoimmune patients.

Peter Tobias, Ph. D., Associate Professor, Department of Immunology and Microbial Science

Dr. Tobias studies the mechanisms by which cells utilize the innate immune system to detect microbes and initiate defensive inflammatory responses. His work has three foci. First, his laboratory seeks to understand the structural features of the Toll like receptors and their allied proteins LBP, CD14, and MD-2, which enable them to bind with high affinity to microbes and their components. Second, he studies the structural changes by which binding of a microbial ligand to the extracellular domain of the receptor leads to signal transduction across the cell membrane and initiation of intracellular signaling cascades. Third, he is interested in the involvement of microbial pathogen receptors in several inflammatory diseases including atherosclerosis.

Bruce E. Torbett, Ph.D., MSPH, Associate Professor, Department of Molecular and Experimental Medicine

Dr. Torbett investigates normal and abnormal (cancer) myeloid development and HIV entry, structural aspects of HIV-1 and drug resistance. The transcription factor PU.1 is a master regulator of hematopoietic and myeloid development and Dr. Torbett continues to define the role of PU.1 and its control of downstream genes in dictating myeloid development and function. The laboratory currently is studying the TREM pathway that is regulated by PU.1 and aims to understand how TREM2 is restricted to macrophages, microglial, dendritic cells, and osteoclasts. Studies are also underway to define how TREM signaling contributes to the functional regulation of differentiated myeloid cells. The laboratory applies a broad range of technologies, including lentiviral gene delivery, transgenic mice, and mass spectrometry for biological applications.

J. Lindsay Whitton, M.D./Ph. D., Professor, Department of Immunology and Microbial Science

Dr. Whitton studies antiviral immunity and viral pathogenesis and new approaches of vaccine development. For studies on pathogenesis, the laboratory employs coxsackievirus type B3 (CVB3) pathogenesis, which is a common cause of myocarditis (heart disease). Dr. Whitton found that one can interrupt certain components of the immune response to relieve myocarditis without compromising the ability of the host to eradicate the infection. The laboratory continues to characterize the underlying mechanisms of coxsackievirus pathogenesis and viral clearance using genetically engineered mouse models that allow temporal and local control of cytokine expression in the heart.