GROWTH FACTORS IN THE ADULT AND AGING BRAIN

Project: Research project

Project Details

Description

During the past decade, it has been recognized that one common pathologic
abnormality that has been observed in diseases that effect the elderly such
as Alzheimer's or Parkinson's disease is premature neuronal degeneration.
Further, it has been demonstrated that specific factors exist which are
responsible for the development, maintenance, and survival of specific
neuronal populations. It has therefore been suggested that the induction
or progression of a neurodegenerative disease process may be due to the
unavailability of a specific trophic factor. Since Parkinson's disease is
characterized by the accelerated degeneration of mesencephalic dopamine
neurons, we have been engaged in studies identifying trophic factors which
are able to enhance the survival of dopamine neurons. We have found that
epidermal growth factor (EGF) and its structural and functional analog,
transforming growth factor-alpha (TGF-alpha), are able to increase the
survival of developing dopamine neurons in vitro. We and others have
evidence that both EGF and TGF-alpha are expressed in dopaminergic
projection sites in mature animals. It has recently been demonstrated that
EGF administration to animals, in which the dopaminergic nigrostriatal
pathway has been transected, is able to increase the number of dopaminergic
fibers. These results suggest that EGF may have trophic effects on
dopamine neurons in mature animals and that lack of this growth factor
could result in the degeneration of dopamine neurons. Other laboratories
have demonstrated that basic fibroblast growth factor (bFGF) and brain
derived neurotrophic factor (BDNF) can also able to provide trophic support
to developing dopamine neurons and to lesioned dopamine neurons in mature
animals. Therefore we propose to study the regulation of gene expression
of each of these growth factor mRNAs in the course of normal brain
maturation, in association with the neurodegeneration that occurs in the
weaver mutant mouse and in response to MPTP toxicity paradigms where
dopamine neurons vary in the ability to recover. In order to determine if
the selective vulnerability of the mesostriatal versus the mesolimbic
dopamine neurons could be explained by different trophic requirements,
studies in the proposal are designed to determine, by in situ
hybridization, if there are differences between dopamine neurons in the
substantia nigra and ventral tegmental area in their expression of these
growth factor receptors. It is anticipated that this anatomical and
quantitative examination of the expression of these putative dopaminergic
growth factors and their respective receptors in normal and
neurodegenerating brains should aid in the characterization of the specific
physiologic functions for these peptides in the trophic support of dopamine
neurons.
StatusFinished
Effective start/end date5/1/924/30/06

Funding

  • National Institutes of Health: $268,056.00
  • National Institutes of Health: $276,031.00

ASJC

  • Medicine(all)

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