Faculty

UW Cardiovascular Pathology Training Program
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Faculty Member	Department/Division	Areas of Interest	Current and Past Fellows
Stephen M. Schwartz, MD, PhD Chair	Pathology; Cardiovascular Pathology Training Program (CVP), Cardiology; Bioengineering	Schwartz Lab	1988-present
Ruedi Aebersold, PhD	Genome Sciences, Proteomics, Institute of Systems Biology, Allergy & Infectious Diseases, Microbiology	Aebersold Group	1991-present
John Albers, PhD	Medicine, Metabolism, Endocrinology & Nutrition, NW Lipid Research Labs	Lipids	1983-present
Joseph A. Beavo, PhD	Pharmacology	Beavo Lab	1987-present
Karin E. Bornfeldt, PhD	Pathology, Molecular & Cellular Biology	Bornfeldt Lab	1999-present
Paul Bornstein, MD	Biochemistry	Bornstein Group	1985-present
Daniel F. Bowen-Pope, PhD	Pathology	Vascular Biology	1984-present
Roger Bumgarner, PhD	Microbiology, Center for Expression Arrays	Bioinformatics	2000-present
Peter H. Byers, MD	Pathology, Medicine, Genome Sciences	Gene mutations	1983-present
William A. Catterall, PhD	Pharmacology	Electrical excitability	1983-present
Alan Chait, MD	Medicine, Metabolism, Endocrinology & Nutrition, Clinical Nutrition Research Unit	Cell biology of atherosclerosis	1991-present
Alexander W. Clowes, MD	Medicine, Vascular Surgery, Pathology	Arterial graft healing	1984-present
Marshall A. Corson, MD	Medicine, Cardiology, HMC	Vascular cell biology	1994-present
Earl W. Davie, PhD	Biochemistry	Davie Group	1988-present
Samir S. Deeb, PhD	Genetics	Deeb Group	1988-present
David Dichek, MD	Medicine; Cardiovascular Research & Treatment; Cardiology; UW Med Center	Dichek Lab	1990-present
Eric O. Feigl, MD	Physiology and Biophysics	Coronary physiology	1982-present
Cecilia M. Giachelli, PhD	Bioengineering, Pathology, UW Engineered Biomaterials Center	Giachelli Lab	1989-present
Gary Gibbons, PhD	Cardiovascular Research Institute, Morehouse School of Medicine	Gibbons Lab	1991-present
John A. Glomset, MD	Medicine, Biochemistry, Metabolism, Endocrinology & Nutrition	Glomset Lab	1990-present
John M. Harlan, MD	Medicine, Hematology, Harborview Med Center	Leukocyte	1987-present
Stephen D. Hauschka, PhD	Biochemistry, Zoology	Hauschka Lab	1987-present
Jay Heinecke, MD	Medicine, Metabolism, Endocrinology, & Nutrition	Heinecke Lab	1986-present
Marshall Horwitz, MD, PhD	Medicine, Genome Sciences, Pathology	Horwitz Lab	1995-present
Gail P. Jarvik, PhD	Medicine, Genome Sciences, Epidemiology	Jarvik Lab	1996-present
David Kimelman, PhD	Biochemistry, Zoology	Kimelman Lab	1990-present
Rachel Klevit, PhD	Biochemistry, Chemistry	Klevit Lab	1986-present
Richard Kronmal, PhD	Biostatistics	Kronmal Lab	1992-present
Renee LeBoeuf, PhD	Public Health and Community Medicine Pathobiology, Public Health Genetics Program	LeBeouf Lab	1993-present
Åke Lernmark, MD	Medicine, Immunology	R H Williams Lab	1979-present
W. Conrad Liles, PhD	Medicine, Allergy & Infectious Diseases	Liles Lab	1996-present
G. Stanley McKnight, PhD	Gene Array Facility, Pharmacology	McKnight Lab	1985-present
Randall T. Moon, PhD	Pharmacology, Howard Hughes Medical Institute	Moon Lab	1982-present
Charles Murry, MD, PhD	Pathology	Murry Lab	1995-present
Neil M. Nathanson, PhD	Pharmacology	Nathanson Lab	1986-present
Deborah Nickerson, PhD	Genome Sciences, Bioengineering, Environmental Genome Project	Nickerson Lab	1996-present
Elaine Raines, MS	Pathology, Russell Ross Endowed Lecture	Atherosclerotic lesions	1989-present
Buddy Ratner, PhD	Bioengineering, Chemical Engineering, UWEB	Biomaterials	1992-present
Michael A. Reidy, PhD	Pathology	Reidy Lab	1986-present
Michael E. Rosenfeld, PhD	Pathobiology, Graduate Program in Nutritional Sciences, Pathology	Rosenfeld Lab	1990-present
Anthony Rossini, ScD	Biostatistics, Medical Education and Biomedical Informatics, Bioinformatics	Rossini Lab	2003-present
Walter L. Ruzzo, PhD	Computer Science & Engineering, Genome Sciences	Ruzzo Lab	1989-present
Daniel E. Sabath, MD, PhD	Laboratory Medicine, Medical Genetics, Hematology	Hematology Lab	2001-present
E. Helene Sage, PhD	Basic Sciences Hope Heart Institute, Biological Structure	Sage Lab	1985-present
Luis Fernando Santana, PhD	Physiology & Biophysics	Santana Lab	1989-present
Lynn M. Schnapp, MD	Medicine, Pulmonary and Critical Care Medicine	Schnapp Lab	1997-present
Phillippe Soriano, PhD	FHCRC, Basic Sciences, Molecular and Cellular Biology	Growth Factors	1989-present
Daniel R. Storm, PhD	Pharmacology	Storm Lab	1982-present
Thomas N. Wight, PhD	Pathology, Molecular and Cellular Biology, UWEB, Diabetes Endocrinology Research Center, Vascular Biology, Hope Heart Institute	Wight Lab	1977-present

CVP Faculty Areas of Interest

Faculty Member

Area of Interest

Ruedi Aebersold, Molecular Biotechnology, Proteomics

The objective of research in our group is the development of new technologies for the comprehensive analysis of regulated biological systems and to apply these technologies to the study of the signal transduction pathways which induce and control the fate of T cells during development and activation. These signal transduction pathways, like other regulated systems, depend on the coordinated expression and activation of multiple genes and their respective products. We are developing new experimental approaches for the identification of the proteins which are part of a particular pathway and for the determination of the function and the state of activity of the identified proteins. Our approach is based on the integration of high resolution proteins and peptide separation techniques with high sensitivity detectors such as mass spectrometers and atomic force microscopes. As the number of the gene sequences determined is rapidly increasing, we anticipate that technologies which focus on the characterization of proteins, i.e., the biological effector molecules and their state of activity will become essential tools for the comprehensive analysis of biological systems.

John Albers, Metabolism, Endocrinology & Nutrition

Elucidation of the role of proteins of lipid transport in lipid and lipoprotein metabolism. Cloning, expression, and gene regulation of the lipid transfer proteins. Development and application of immunoassays for proteins of lipid transport. Pathophysiology of lipid transport in subjects with genetic hyperlipidemia and premature vascular disease.

Joseph A Beavo, Pharmacology

Cyclic nucleotides are soluble second messengers found in all tissues throughout the body. Many drugs, hormones, and other agents modify physiological processes causing changes in the steady state levels of cAMP and cGMP in cells. The amplitude and duration of these second messenger signals can be controlled by altering the activity of the cyclic nucleotide phosphodiesterases (PDEs) that degrade them. These PDEs regulate many signaling pathways. For instance, the transduction of photon capture in the outer segment of a photoreceptor to changes in neurotransmitter release from the inner segment of this neuron is known to require PDE6. Regulation of aldosterone production by atrial natriuretic peptide and regulation of platelet aggregation by endothelial relaxation factor also depend on different PDEs. Various drugs such as Viagra can selectively inhibit individual PDE isozymes and therefore have unique specific effects, suggesting different physiological roles for each PDE

Karin E Bornfeldt, Pathology

My laboratory focuses on diabetes-accelerated cardiovascular disease (atherosclerosis) and the intracellular signal transduction pathways involved. People with diabetes have a higher risk of developing cardiovascular disease, and the cardiovascular disease occurs earlier in life than in people without diabetes. Diabetes-accelerated atherosclerosis can lead to early heart attack, stroke, and amputation of legs and feet. We have recently shown that diabetes induces proliferation of both arterial smooth muscle cells and macrophages in lesions of atherosclerosis. This effect is due to hypoinsulinemia and/or hyperglycemia.

Paul Bornstein, Biochemistry

The major interests of the laboratory include 1) studies of the effects of matricellular proteins, primarily thrombospondins (TSPs) 1 and 2, on cell function and cell-matrix interactions, and 2) transcriptional regulation of the type I collagen genes.

The following projects are under active investigation:

• The role of matrix metalloproteinases in the adhesive defect of dermal fibroblasts from TSP2-null mice.

• The molecular and cellular basis for the bleeding diathesis in TSP2-null mice.

• Studies of TSP1/TSP2 double-null mice.

• The use of local gene therapy to regulate expression of TSP2 in wound healing and in the foreign body reaction.

• The regulation of marrow stromal cell proliferation and bone growth by TSP2.

• The mechanism of inhibition of angiogenesis by TSP2.

• Studies of the transcriptional regulation of the a1(I) collagen gene in mice by generation of targeted promoter and intronic mutations.

• Analyses of type I collagen structure and function in mice with a targeted deletion of exon 2 in the a1(I) collagen gene.

Daniel F Bowen-Pope, Molecular and Cellular Biology

My general interests are in vascular biology and molecular regulation of vascular (and other tissue) response to injury. My lab currently has three project areas:

1) Using a system of conditional reporters and cell-type-specific markers in transgenic mice to test the hypothesis that new blood vessel formation and remodeling in adult tissue includes vascular cell derivation from undifferentiated “stem cells”, and “transdifferentiation” from other cell types, in addition to the canonical origins from proliferation and migration of existing vascular cells.

2) We have developed a system for regulating apoptosis of vascular smooth muscle cells (SMCs) in vivo, and have used this system to determine that SMC apoptosis initiated by FADD overexpression includes a specific program of expression of pro-inflammatory genes that results in recruitment of macrophages. Binding of Fas ligand (FasL) to cultured human SMCs initiates a comparable program. We are attempting to further define this program of gene expression, determine the signaling mechanisms through which it is regulated, and further investigate the consequences of SMC apoptosis in vivo.

3) PTPRQ is a protein tyrosine phosphatase (PTPase)-like protein that we initially identified and cloned based on its upregulation in a rat model of renal injury. We have found that PTPRQ is a very unusual member of the PTPase superfamily in that its biological activity is due to its activity as a phosphatidylinositol phosphatase (PIPase) rather as a PTPase. PTPRQ has broader PIPase activity than does the tumor suppressor PTEN, the first PTPase shown to have PI 3-phosphatase activity, but it has a more restricted pattern of expression. The receptor-like form of PTPRQ protein appears to be largely localized to specialized regions of non-proliferating cell types (including podocytes, inner ear hair cells and Sertoli cells) that are involved in cell-cell or cell-matrix interactions. Targeted disruption of PTPRQ in mice results in deafness and altered response to renal injury. We are testing hypothesis that subcellular localization of PTPRQ in specialized membrane regions plays a role in regulation of local membrane PIP composition, and that this plays a role in regulating specialized cell architecture and function by altering the local binding and/or activity of PIP-binding proteins.

Roger Bumgarner, Microbiology

Bioinformatics. During the past four years, my research group has focused on the development of software and databases to analyze and store microarray data. We have developed tools for image analysis, normalization, statistical analysis of replica data and the selection of differentially expressed genes. In addition, we have developed a database to store and publish microarray data. Current research interests in this area are centered around the development of improved pattern recognition algorithms and the integrated storage and analysis of various forms of functional genomic data (expression array, proteomics, translation state array, sequence data etc.).

Technology development. The development and design of oligo arrays: Our interest in this area involves producing arrays for species for which there are no commercially available sources and in the development of arrays that will represent known splice variants of eukaryotic genes.

Proteomics. We are developing methods and protocols for 2-D, two color gel analysis that will allow one to measure protein levels in two or more samples.

Biological Applications

Translational control. In collaboration with Dr David Morris we are applying microarrays to the study of translational control. This involves extracting RNA from different polysome fractions and hybridizing this RNA to arrays in order to measure the distribution of all genes in the polysome fractions.

Host-virus interaction. The primary focus of our biological research is the analysis of host gene expression in infected cells. We are developing a database compendium of both internally and externally generated microarray data from host cells infected with a broad range of viruses and viral strains. Our interest in the analysis of such data is to identify common pathways in the host cell that are targeted by viruses and to look for convergent evolution of viral mechanisms that avoid the hosts innate immune response.

Peter H Byers, Pathology, Genome Sciences

We are pursuing several lines of research: the characterization of mutations in type I collagen genes that give rise to forms of osteogenesis imperfecta and other disorders, the identification and characterization of mutations in type III collagen genes which give rise to Ehlers-Danlos syndrome type IV, identification of proteins in the intracellular and extracellular processing pathways that identify abnormal collagen proteins, the mechanisms of mRNA processing in collagen genes, the dispersion of repetitive elements within the COL3Al gene of type III collagen, and mutations in the type V collagen genes which give rise to milder forms of EDS.

The majority of mutations in the COL1Al and COLlA2 genes that cause OI result in substitution for glycines within the triple helix. Most of the remainder alter splice sites. Our studies of the mutations suggest that in some instances the order of exon splicing may determine the effects of splice mutations; as a consequence we are studying the order of intron removal in such cell strains. One of the most puzzling aspects of OI has been the failure to identify mutations in all affected individuals. Using long amplification regions, we have noted low level splice defects in some such patients that result in the production of only a small amount of abnormal molecules due to the presence of 5-10% abnormal mRNA species as a consequence of mutations outside the canonical splice site sequences.

We have now characterized almost mutations in our families with EDS type IV. These are more heavily weighted to point mutations that result in substitutions for glycine residues within the triple helix of the molecule than mutations that alter splice site integrity. Some of these mutations prohibit mRNA transport from the nucleus when introns that contain termination codons are included. These findings suggest that there is a link between splicing and nuclear recognition of premature termination codons that may be different from the recognition process that leads to cytoplasmicnonsense-codon mediated mRNA decay. The mechanisms of recognition of these structures is being pursued.

Similar approaches are being taken to disorders which result from several other genes involved in connective tissue biogenesis.

William A Catterall, Pharmacology

The Molecular Basis of Electrical Excitability:

Electrical impulses generated by nerve, skeletal muscle, and heart muscle cells play an essential role in coordination of most physiological functions and in learning and memory in the central nervous system. Research in this laboratory is focused on understanding the molecular basis of electrical excitability, the regulation of electrical excitability by physiological stimuli, and the mechanism of action of neurotoxins and drugs which alter electrical excitability. Neurotoxins and drugs have been used as specific molecular probes to identify, purify, and characterize voltage-sensitive sodium and calcium channels from mammalian brain and skeletal muscle. The function of these purified ion channels has been restored by incorporation into phospholipid bi-layer membranes and this experimental system has been used to analyze the relationship between channel structure and function on the molecular level.

Cloned DNA probes which encode the structure of these ion channels, site-directed mutagenesis and functional expression, and site-directed antibodies which recognize specific peptide segments are being used to probe the molecular mechanisms of ion channel function and to examine the mechanisms of regulation of biosynthesis, assembly, and localization of ion channels during neural development in vivo and in cell culture. Specific protein segments which form the voltage sensors and inactivation gate of the sodium channel have been defined and sites of phosphorylation by specific protein kinases which modulate sodium and calcium channel function have been identified. Regulation of ion channel properties by physiological and hormonal stimuli is of great interest as a potential mechanism of modulation of information processing, learning, and memory in the central nervous system.

Clinically important drugs, including local anesthetics, anti-arrhythmics, anti-epileptics, and calcium antagonists alter the properties of voltage-sensitive ion channels. We are currently investigating the sites and mechanisms by which these drugs alter the properties of ion channels, taking advantage of cultured cell systems, specific antibodies and neurotoxins, purified channel preparations, and cloned cDNAs to attempt to define the mechanism of drug action at the molecular level and identify common themes which may be important in development of new therapeutic agents. Recent work has led to the identification of the receptor sites for the calcium antagonist drugs on calcium channels and the receptor sites for local anesthetic drugs and multiple neurotoxins on sodium channels.

Alan Chait, Metabolism, Endocrinology & Nutrition

The focus of the laboratory is on investigation of the cell biology of atherosclerosis, with particular emphasis on the roles of atherogenic lipoproteins and diabetes mellitus. The molecular determinants of lipoprotein retention by extracellular matrix molecules secreted by vascular smooth muscle cells and macrophages is being studied using cell culture techniques, animal models and specimens of human arteries. Studies to understand the regulation of proteoglycan synthesis by native and modified lipoproteins and by factors associated with the diabetic state, and how modulation of proteoglycan synthesis influences lipoprotein retention also is being evaluated. Research also is being performed to determine the mechanisms and roles of lipoprotein modification, especially oxidative modification, on atherogenesis.

Alexander W. Clowes, Vascular Surgery

Research Interests: Mechanisms of arterial graft healing, inhibition of restenosis, atherosclerosis and plaque progression - supported by MERIT award and other funding from NIH.

Clinical Interests: Peripheral vascular surgery; mechanisms of stenosis/restenosis after vascular reconstruction.

Marshall A Corson, Cardiology

Areas of Clinical Expertise: General cardiology and cardiac catheterization, cardiovascular risk modification

Current Research Interests:
Regulation of vascular cell biology by protein phosphorylation.

Development of new therapeutic options for treatment of coronary artery disease, e.g. antiplatelet and antibiotic agents.

Earl W Davie, Biochemistry

The research program of Dr. Earl Davie and his group deals primarily with proteins involved in blood coagulation and fibrinolysis. In this research, the structure and function of a number of proteins are studied and their role in the formation of fibrin examined. X-ray diffraction studies are carried out on a recombinant fragment of the gamma chain of human fibrinogen and detailed molecular interactions at the initial stages of fibrin polymerization are examined. Two novel proline-rich γ-carboxyglutamic acid-containing proteins have been identified by homologous c