Molecular and transgenic studies on tyrosine hydroxylase gene regulation: Anatomical, developmental and functional analyses.
Item
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Title
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Molecular and transgenic studies on tyrosine hydroxylase gene regulation: Anatomical, developmental and functional analyses.
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Identifier
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AAI9732949
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identifier
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9732949
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Creator
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Min, Nan.
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Contributor
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Adviser: Richard Bodnar
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Date
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1996
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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, Molecular | Psychology, Physiological
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Abstract
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Catecholaminergic neurotransmission regulates many physiological functions in the central and peripheral nervous system. Catecholamines (CA) are important in the modulation of blood pressure, responses to stress, motor function, memory, learning, mood, appetite, and the mediation of psychotropic drug action. From its precursor tyrosine, CA biosynthesis occurs via a series of enzymatic reactions, the first and rate-limiting step catalyzed by tyrosine hydroxylase (TH). Drugs that have major effects on CA neurotransmission are being used in the treatment of psychiatric and neurological conditions, such as schizophrenia, major affective disorders and Parkinson's disease. Pharmacological approaches may lack receptor specificity and cross-react across different neurotransmitter systems. Thus, I used molecular approaches to study CA neurotransmission function by investigating in vivo regulation of the TH gene. TH undergoes precise temporal, spatial and functional regulation at the transcriptional level.;To identify genetic regulatory elements of the rat TH gene that contribute to the regulation of its expression in CA cells, three fusion genes containing 0.15 kb, and 2.4 kb and 9.0 kb of the 5{dollar}\sp\prime{dollar} flanking sequences of the rat TH gene linked to the E. coli lacZ ({dollar}\beta{dollar}-galactosidase) reporter gene were microinjected into the pronuclei of fertilized embryos to generate transgenic mice. Analyses of the transgene expression in the CNS revealed that the 9.0 kb promoter, but not the smaller sequences, drove the reporter expression to catecholamine cells in the CNS of transgenic mice. In addition, the 9 kb TH promoter also directs CA cell lineage-specific expression of lacZ during embryogenesis. Thus, it appears to contain the cis-acting DNA elements necessary to interact with the environmental cues that specify differentiation. Finally, these TH 5{dollar}\sp\prime{dollar} sequences are also sufficient to mediate cell-specific trans-synaptic regulation of reporter gene expression in two paradigms: downregulation of expression in the glomerular layer of the olfactory bulb and upregulation of expression in the locus ceruleus and VTA after reserpine administration. Thus, the 9.0 kb of rat TH 5{dollar}\sp\prime{dollar} flanking sequences contain the important DNA elements to mediate appropriate spatio-temporal and trans-synaptic expression of a reporter gene to catecholamine cell in the CNS of transgenic mice.
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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.
