This is a request for an NIMH RSDA level 11 award that will allow me to keep my focus on research, and to develop new skills that will improve my ability to apply molecular biology to the nervous system. The present proposal is part of an effort to complete a detailed analysis of the molecular mechanisms regulating expression of the proenkephalin gene. Understanding the mechanisms which determine neural phenotypes during, development and which permit subsequent plasticity are among the central goals of neuroscience. At a fundamental level, both of these processes depend upon differential control of gene expression. I have been investigating the molecular mechanisms regulating expression of neurotransmitter genes, focusing on the gene encoding the opioid peptide precursor, proenkephalin. This ene is an ideal model because it is well studied, physiologically important, has an interesting pattern of cell-type specific expression, and is highly regulated by neurotransmitters, electrical stimulation, seizures, arid psychotropic drugs. This grant application requests support to continue on going studies of the mechanisms by which proenkephalin gene expression is regulated at the level of cis-regulatory elements and transacting factors, but shifting the emphasis to the regulation of cell type specific expression. It is proposed to apply these studies to the nervous system by producing transgenic mice. Because the production and detailed histologic analysis of transgenic mice are new techniques to me, this proposal will contribute significantly to my career development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02MH000892-03
Application #
3070261
Study Section
Research Scientist Development Review Committee (MHK)
Project Start
1990-08-01
Project End
1995-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Kosofsky, B E; Genova, L M; Hyman, S E (1995) Substance P phenotype defines specificity of c-fos induction by cocaine in developing rat striatum. J Comp Neurol 351:41-50
Konradi, C; Cole, R L; Green, D et al. (1995) Analysis of the proenkephalin second messenger-inducible enhancer in rat striatal cultures. J Neurochem 65:1007-15
Kosofsky, B E; Genova, L M; Hyman, S E (1995) Postnatal age defines specificity of immediate early gene induction by cocaine in developing rat brain. J Comp Neurol 351:27-40
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Borsook, D; Falkowski, O; Burstein, R et al. (1994) Stress-induced regulation of a human proenkephalin-beta-galactosidase fusion gene in the hypothalamus of transgenic mice. Mol Endocrinol 8:116-25
Borsook, D; Konradi, C; Falkowski, O et al. (1994) Molecular mechanisms of stress-induced proenkephalin gene regulation: CREB interacts with the proenkephalin gene in the mouse hypothalamus and is phosphorylated in response to hyperosmolar stress. Mol Endocrinol 8:240-8
Symes, A; Lewis, S; Corpus, L et al. (1994) STAT proteins participate in the regulation of the vasoactive intestinal peptide gene by the ciliary neurotrophic factor family of cytokines. Mol Endocrinol 8:1750-63
Schwarzschild, M A; Dauer, W T; Lewis, S E et al. (1994) Leukemia inhibitory factor and ciliary neurotrophic factor increase activated Ras in a neuroblastoma cell line and in sympathetic neuron cultures. J Neurochem 63:1246-54
Symes, A J; Rao, M S; Lewis, S E et al. (1993) Ciliary neurotrophic factor coordinately activates transcription of neuropeptide genes in a neuroblastoma cell line. Proc Natl Acad Sci U S A 90:572-6

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