Characterization and regulation of basement membrane heparan sulfate proteoglycan.
Item
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Title
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Characterization and regulation of basement membrane heparan sulfate proteoglycan.
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Identifier
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AAI9510656
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identifier
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9510656
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Creator
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Eisler, Jesse Grant.
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Contributor
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Adviser: Howard Fillit
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Date
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1994
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Neuroscience
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Abstract
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Heparan sulfate proteoglycans (HSPG) are integral components of the extracellular matrix of basement membranes (BM). BMs may support polarized cells, being deposited at the basal side of endothelial or epithelial cells, or they may surround such cells as muscle cells, or neurons. As constituents of the BM, HSPGs play a role in several important physiologic processes, including BM structure and permeability, regulating the activity of protease inhibitors and growth factors, and they have been implicated in the pathogenesis of Alzheimer's Disease. Despite their significance we do not have a complete understanding of the structure of all basement membrane HSPGs, or of the factors that may regulate the metabolism of these molecules.;We examined the relationship between the two major forms of basement membrane HSPGs, perlecan and vascular HSPG (vHSPG). Immunological methods revealed a high degree of antigenic uniqueness, and protein precursor studies demonstrated different precursor sizes for the two basement membrane HSPGs. The data suggests that these molecules are unique gene products. While the cDNA sequence of perlecan is known, there is no DNA sequence available for vHSPG to date, and the elucidation of the exact relationship between perlecan and vHSPG awaits this information.;The regulation of basement membrane proteoglycans produced by mouse endothelial cells exposed to various relevant factors was examined. Our analysis employed RNA analysis, ion exchange, gel filtration, and A4-affinity chromatography. We determined that the relative proportion of proteoglycans with high net negative charges was susceptible to alteration when cells were treated with IL-1{dollar}\beta{dollar}, TGF-{dollar}\beta{dollar}, and low molecular weight hyaluronic acid, whereas the proteoglycans with a lower net negative charge were not altered significantly. IL-1{dollar}\beta{dollar} (10 ng/ml) increased the proportion of secreted proteoglycans, TGF-{dollar}\beta{dollar} (5 ng/ml) increased the relative amount of cellular proteoglycans, while low molecular weight hyaluronic acid had the opposite effect and decreased the amount of cellular proteoglycans with a high net negative charge. These results suggest that proteoglycans are subject to specific regulation by various cellular/extracellular factors, and fluctuations in the levels of these factors that can occur in disease processes may have important consequences for the regulation of proteoglycans.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
