Interactions of growth factors and neuroactive amino acids in normal and abnormal development of the central nervous system.
Item
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Title
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Interactions of growth factors and neuroactive amino acids in normal and abnormal development of the central nervous system.
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Identifier
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AAI9917647
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identifier
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9917647
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Creator
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El Idrissi, Abdeslem.
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Contributor
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Adviser: Ekkehart Trenkner
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Date
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1999
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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 | Biology, Cell | Health Sciences, Pathology | Biology, Molecular
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Abstract
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In the developing nervous system, individual neurons constantly receive inputs from their external environment. The combinatorial effects of these signals determine the structure and function of particular neurons. In this study, we used primary cultures of cerebellar granule cells (CGCs) as a model system for the study of the interactions between growth factors and neuroactive amino acids. The intrinsic properties of this system are very advantageous for such a study, particularly with regard to developmental stages, which take place predominately postnatally.;We found that growth factors and neuroactive amino acids play a very important role in CGC development in vitro, through regulation of the survival and function. The survival-promoting effects of these signaling molecules were contingent on their balanced interactions.;Other conclusions that stem from this study is that neurons use alternative signaling pathways to maintain their survival and function depending on their developmental stages, their responsiveness to a particular factor, and the availability of these signaling molecules in the external environment.;CGCs use glutamate as their primary neurotransmitter. The effects of glutamate were concentration-dependent. While low concentrations promoted cell survival, high concentrations induced excitotoxic cell death. Glutamate-induced excitotoxicity was mediated through neuronal energy-depletion and perturbation of calcium homeostasis. Because calcium ions play a pivotal role during development and maintenance of neuronal function, regulation of calcium homeostasis is a crucial event. In this study, we found that one common denominator in the function of bFGF and taurine was the restoration of calcium homeostasis and the regulation of calcium-dependent reactions.;Neuronal energy metabolism is recognized as one of the fundamental determinants of cell survival. All processes central to neuronal function depend on energy. The vulnerability of CGCs to glutamate toxicity was energy-dependent. Under conditions that compromised neuronal energy, glutamate-toxicity was enhanced. Growth factors and taurine increased mitochondrial function and prevented excitotoxicity.;In conclusion, the net cellular effects of glutamate are modulated by the presence of taurine and growth factors. Thus, the cascade of events culminating in a decreased calcium response to glutamate and an increased neuronal energy metabolism, could represent a mechanism by which taurine and growth factors prevent glutamate excitotoxicity.
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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.
