Novel modulation of a lipid second messenger as a function of neurotrophin receptors.
Item
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Title
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Novel modulation of a lipid second messenger as a function of neurotrophin receptors.
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Identifier
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AAI3008838
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identifier
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3008838
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Creator
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Kagan, Terri.
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Contributor
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Adviser: Zahra Zakeri
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Date
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2001
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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, Molecular | Biology, Neuroscience
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Abstract
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Ceramide is a lipid second messenger involved in the propagation of diverse signaling pathways that ultimately lead to either differentiation or apoptosis in a cell specific manner. Since two distinct pathways (SM hydrolysis or neosynthesis) can generate endogenous ceramide, its origination may be vital to its downstream signaling activity. In this study we have investigated the role of ceramide in the induction of differentiation and cell death in the rat pheochromocytoma (PC12) cell line, with specific reference to its origin.;Since the PC12 cell fine responds to nerve growth factor (NGF) by expressing a neuronal phenotype, we first asked if ceramide mediates differentiation in response to NGF and whether the cell's expression of neurotrophin receptors affects its ability to generate ceramide. We established that NGF-induced PC12 cell differentiation activates both ceramide pathways but requires only SM hydrolysis, and that overexpression of the high affinity p140trkA NGF receptor results in a cell that requires both ceramide pathways to generate less ceramide in response to NGF. We further established that p140trkA overexpressing cells (TrkA) under-express the low affinity p75NTR receptor. We next determined that apoptosis in neuronal PC12 cells induced by NGF depletion is mediated overexpressing cells (TrkA) under-express the low affinity p75NTR receptor. We next determined that apoptosis in neuronal PC12 cells induced by NGF depletion is mediated by ceramide synthesis, while both pathways mediate ethanol-induced apoptosis. Similarly, we demonstrated that TrkA cells require both pathways but generate smaller amounts of ceramide in response to either NGF depletion or ethanol. We next looked to the mitochondria as a possible downstream target of ceramide. We found that differentiation always accompanied mitochondrial hyperpolarization while apoptosis involved loss of either mitochondrial integrity or enzyme activity. We also established that TrkA cells exhibit mitochondrial hyperpolarization and/or protection against loss of mitochondrial integrity and function in response to inducers of cell death. Finally we examined the ability of the mitochondrial coenzyme CoQ10 to interact with the apoptotic machinery. We found that similar to TrkA overexpression, exogenous CoQ10 both inhibits ceramide synthesis and prevents loss of mitochondrial integrity and function. Finally, we present a model which suggests that neurotrophin receptors may interact with the apoptotic machinery upstream of the mitochondria, blocking apoptosis through modulation of downstream sphingolipid generation and mitochondrial function.
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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.
