Mathematical/kinetic models for low density lipoprotein pathway in non-hepatic human cells (using historic experimental data on human fibroblasts).
Item
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Title
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Mathematical/kinetic models for low density lipoprotein pathway in non-hepatic human cells (using historic experimental data on human fibroblasts).
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Identifier
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AAI9224833
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identifier
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9224833
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Creator
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Lim, Kwang-Hee.
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Contributor
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Adviser: David S. Rumschitzki
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Date
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1992
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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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Engineering, Chemical | Chemistry, Biochemistry | Biophysics, General
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Abstract
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The goal of this thesis is to kinetically model the cellular low density lipoproteins (LDL) pathway. Such quantitative kinetic modeling has the potential to play a role in the development of an overall transport and reaction theory of lipoprotein cholesterol in and through the artery wall.;Part One focuses exclusively on the uptake and degradation of LDL using the historical human fibroblast-derived data of Brown and Goldstein and of other groups. For these data, unlike for data taken on (bovine) smooth muscle cells, it appears necessary to explicitly account for the transfer of cell surface-mobile LDL receptors to receptors bound to coated pits. In addition, kinetic analysis suggests that receptors that have bound LDL molecules before attaching to coated pits have a significantly reduced rate of subsequently becoming attached to coated pits. A closer analysis, both in terms of an order of magnitude calculation and of two detailed models that do not a priori assume diffusion control, reveals, however, that diffusion seems to be too fast to account for the kinetically-determined parameters. One possible explanation, which the models herein support, is that this process is primarily binding, rather than diffusion controlled.;Part Two moves on to examine the regulation processes that such cells use to avoid a shortage or an over-accumulation of cholesterol.;We propose kinetic models to account for each of the regulatory processes and use available data to test these models and to determine their parameters. The models for the control of cellular de novo cholesterol synthesis and for the total receptor tally are gene-level-based, as opposed to that for cholesterol esterification. Its model has the novel feature that LDL-derived cholesterol that has recently entered via the receptor pathway is postulated to be able to expanding the size of the esterifiable cholesterol pool and thereby controlling the rate of esterification. This model turns out to be capable of explaining a number of experimental observations. Finally, the combined model seems to be quite capable of predicting experimental results even when all of the regulatory processes are at play. (Abstract shortened with permission of author.).
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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.
