PACAP REGULATION OF NEUROGENESIS AND SURVIVAL

Project Details

Description

While the growth of neuronal population has been well-characterized in
vivo, underlying molecular mechanisms remains undefined. The goal of
this proposal is to define the role of PACAP (pituitary adenylate cyclase
activating peptide) in regulating the three principal mechanisms
contributing to neuronal population growth including 1) stimulating
mitosis of precursor or neuroblasts, 2) enhancing survival of
proliferating precursors and 3) promoting longer-term survival through
action of target-derived neurotrophic factor s. PACAP may be critical
to normal brain development, since this neuropeptide influences
neurogenic and survival of multiple prenatal and postnatal as well as
peripheral and central populations.

Our specific aim are to define the effects of PACAP on neuroblast mitosis
and survival as well as expression of the trk family mRNA's. Second,
characterized the effect of PACAP on second messenger systems: cAMP and
phosphatidyl inositol (PI) metabolism. Third, define dht regulation and
expression of PACAP protein and mRNA in the neurogenetic populations, and
characterized peptide autocrine and autoregulatory activity. Fourth,
characterized PACAP induction of DNA binding activities that interact
with cAMP response elements (CRE's) and other DNA sites in target
neuronal gene promoter.

Our strategy employs pure populations of mitotic neuroblasts from
embryonic sympathetic and sensory ganglia, cerebral cortical
neuroepithelium and postnatal cerebellar cortex to identity population-
specific and age-dependent PACAP regulation. We examine mitogenic and
trophic effects by assaying cell number, [3H]thymidine incorporation, and
neurite outgrowth. cAMP and PACAP protein will be assessed y
radioimmunoassay an PI metabolism by ion-exchange chromatography. mRNA;s
will be assayed by Norther analysis. PACAP induction of population-
specific binding activities will be characterized by gel retardation,
DNAse I footprinting, and UV crosslinking procedures.

By characterizing PACAP actions in peripheral and central neurogenetic
populations, we many define mechanisms by which the single peptide,
PACAP, differentially regulates population-specific neurogenesis and
survival. Hopefully we may learn how extracellular signals, acting via
second messenger and transcriptional pathways, alter neuroblast division,
survival and trophic factor receptor expression to generate diverse
neuronal populations. Insight into second messenger and transcription
pathways underlying PACAP mitogenic and trophic activity may identify
loci where disease processes intervene to produce dysraphic sates,
holoprosencephaly, and systems disorders.
StatusFinished
Effective start/end date1/1/942/28/10

Funding

  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $225,152.00
  • National Institute of Neurological Disorders and Stroke: $316,029.00
  • National Institute of Neurological Disorders and Stroke: $231,884.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $306,864.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $4,680.00
  • National Institute of Neurological Disorders and Stroke: $306,864.00
  • National Institute of Neurological Disorders and Stroke: $323,634.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $323,634.00

ASJC

  • Psychiatry and Mental health
  • Genetics
  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Molecular Biology
  • Neuroscience(all)
  • Cell Biology

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