This is a request for an ADAMHA Research Scientist Development Award, level II. The broad objectives of the research are to characterize the mechanisms which mediate activity-dependent changes in neurotrophic factor gene expression in the adult brain and to evaluate functional consequences of altered expression of the NGF-like neurotrophins following seizure activity. Prior studies by the applicant have demonstrated that seizures alter levels of mRNA for nerve growth factor (NGF) and the structurally related neurotrophins brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) in adult rat brain. In the proposed studies, molecular biological techniques (in situ hybridization, S1 nuclease protection assay, run-on assay) will be used to determine i) if the different mRNAs are colocalized and differentially regulated within individual neurons, ii) if mRNA synthesis is altered following seizure, iii) if growth factor mRNA changes follow, and are dependent upon, increases in c-fos expression, iv) if activity-dependent increases in NGF mRNA and BDNF mRNA become refractory to repeated stimulation, v) if changes in NT3 mRNA are linked to changes in BDNF mRNA and NGF mRNA in a variety experimental paradigms, vi) if seizures stimulate increases in the expression of interleukin-1beta mRNA in forebrain that might play a role in later increases in NGF mRNA expression, and vii) if seizure-induced changes in NGF and BDNF mRNA lead to changes in trophic activity within the forebrain. The training goal for the applicant will be to learn and gain experience in the use of molecular biological techniques needed to support in situ hybridization procedures, to prepare, subclone, and characterize new cDNAs, and to assay levels of mRNA synthesis. This is to be accomplished through increased time working in the laboratory with collaborators on the U.C.I. campus. The long range goals of the research program are i) to further rely on these powerful technical capabilities to independently study the role of activity dependent neuronal gene expression in normal brain function and ii) to identify lines of trophic communication in brain which are necessary for normal function and might be manipulated to promote neuronal viability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02MH000974-04
Application #
2240250
Study Section
Research Scientist Development Review Committee (MHK)
Project Start
1992-05-01
Project End
1997-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
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Guthrie, K M; Woods, A G; Nguyen, T et al. (1997) Astroglial ciliary neurotrophic factor mRNA expression is increased in fields of axonal sprouting in deafferented hippocampus. J Comp Neurol 386:137-48
Conner, J M; Lauterborn, J C; Yan, Q et al. (1997) Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport. J Neurosci 17:2295-313
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Gold, S J; Hennegriff, M; Lynch, G et al. (1996) Relative concentrations and seizure-induced changes in mRNAs encoding three AMPA receptor subunits in hippocampus and cortex. J Comp Neurol 365:541-55
Lauterborn, J C; Rivera, S; Stinis, C T et al. (1996) Differential effects of protein synthesis inhibition on the activity-dependent expression of BDNF transcripts: evidence for immediate-early gene responses from specific promoters. J Neurosci 16:7428-36
Lauterborn, J C; Bizon, J L; Tran, T M et al. (1995) NGF mRNA is expressed by GABAergic but not cholinergic neurons in rat basal forebrain. J Comp Neurol 360:454-62
O'Connor, L T; Lauterborn, J C; Smith, M A et al. (1995) Expression of agrin mRNA is altered following seizures in adult rat brain. Brain Res Mol Brain Res 33:277-87

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