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Inflammation/ Atherosclerosis | |
Immunology | |
Cancer |
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Neurosciences | |
Aging | |
Genetics |
Research Area: Regulation of Monocyte Endothelial Interactions Research Interests: My research deals with the events mediating chronic inflammatory processes such as occur in atherosclerosis, cancer and rheumatoid arthritis. We employ cell, molecular and biochemical methods to the study the mechanisms by which oxidized phospholipids activate endothelial cells to bind monocytes and mediate monocyte entry into tissues. HPLC and Mass Spectroscopy have been used to identify several oxidized phospholipids that can activate endothelial cells in culture to bind monocytes. We have shown that these oxidized phospholipids are increased in atherosclerotic lesions isolated from mice and rabbits. These lipids appear to interact with an previously unidentified G-Protein coupled receptor/s. A major aim of our current students is to identify the receptor/s using several cloning approaches including oocyte and mammalian expression systems. We have also shown that oxidized phospholipids activate endothelial cells in culture to deposit a particular alternative splice form of fibronectin on the apical surface; monocytes are able to bind to this form of fibronectin. We now propose to use gene targeting strategies to determine whether this form of fibronectin is important in atherosclerosis in mice. For these studies a dominant negative and a mutational approach will be utilized. Selected Publications: Parhami F, Fang ZT, Fogelman AM, Andalibi A, Territo MC and Berliner JA. Minimally Modified Low Density Lipoprotein-induced inflammaory responses in endothelial cells are mediated by cyclic adenosine monophosphate. J Clin Invest 92: 471-478, 1993. Watson AD, Leitinger N, Navab M, Faull KF, Witztum JL, Subbanagounder G, Fogelman AM and Berliner JA. Structural Identification by Mass Spectrometry of oxidized phospholipids in Minimally Oxidized LDL that induce monocyte-endothelial interactions and evidence for their presence in vivo. J. Biol. Chem. 272:13597-13607, 1997. Research Area: Atherosclerosis/Transplantation Pathology/Cardiovascular Pathology Research Interests: Research includes study of cardiovascular diseases in man and experimental models. Most recent studies involve transplantation pathology, arrhythmogenesis, and pathology of intravascular interventional therapy. Research Area: Antimicrobial Petides and Host Defense Research Interests: Living organisms selectively restrict the colonization of their surfaces by microbes, and actively resist the penetration of microbes into deeper tissues. Among the chemical substances that participate in microbistatic and microbicidal activity on body surfaces and in tissues, antimicrobial peptides (also called "natural antibiotics", herein defined as polypeptides smaller than 100 amino acids) are both abundant and ubiquitous but their role in resistance to infections is only beginning to be appreciated. Antimicrobial peptides have been found in amoebae, plants, insects and other invertebrates and in vertebrates, including humans. In vertebrates, antimicrobial peptides are not only abundant components of cytoplasmic granules in phagocytes but are also secreted by epithelial cells. The two major classes of human antimicrobial peptides are defensins and cathelicidins. We study the contribution of these and other antimicrobial peptides to human host defense. We isolate antimicrobial peptides from phagocytes or epithelial secretions, characterize their composition and activity, and study the regulation of their synthesis, posttranslational processing and release. We also express exogenous antimicrobial peptides in mice and study the effects of these peptides on their host defense function. A recent focus of our laboratory is the pathogenesis of cystic fibrosis, a disease where antimicrobial peptide function is impaired due to abnormalities in the composition of airway secretions. For similar reasons, we are also interested in the pathogenesis of recurrent infections of urogenital mucosal surfaces. Research Area: Nuclear hormone receptors Research Interests: The nuclear hormone receptors are a family of ligand-activated transcription factors that play diverse roles in mammalian physiology. While it has long been recognized that these proteins are central to development and homeostasis in vertebrate organisms, recent work has begun to define an unexpected role for members of this superfamily in human disease. Obesity, diabetes and cardiovascular disease are the leading causes of morbidity and mortality in industrialized societies. The common thread that links these disorders is a dysregulation of lipid metabolism. Recent years have seen a new paradigm emerge for the transcriptional regulation of metabolic pathways with the discovery of nuclear receptors that are activated by lipids. Included in this group are PPARgamma, which is activated by fatty acids, and LXR, which is activated by cholesterol metabolites. These receptors modulate differentiation and lipid homeostasis in multiple cell types, and the pathways they control have critical links to metabolic disease. Our present focus is on defining the role of the PPAR and LXR signaling pathways in macrophages and adipocytes. We use a combination of molecular biology, mouse genetics and gene array technology. Our goal is to understand the importance of these receptors in both normal physiology and diease. As ligand-activated transcription factors, nuclear receptors make ideal drug targets. Recent work suggests that both PPARg and LXR may represent targets for therapuetic intervention in atherosclerosis. |
