CONTROL OF NERVE GROWTH FACTOR METABOLISM

  • Zaborszky, Laszlo (PI)
  • Trugman, Joel (PI)
  • Zaborsky, Laszlo (PI)
  • Tuttle, Jeremy (PI)
  • Bennett, James (PI)
  • BENNETT, JAMES PEPPER (PI)
  • Wooten, Frederick (PI)

Project Details

Description

Neurons depend upon proteins known as neurotrophic factors for normal
development and maintenance. The prototypial example is nerve growth
factor (NGF), now known to be one member of a group of at least three
related, very potent and widespread neurotrophin proteins. While NGF has
been studied intensively, little is known about NGF synthesis by the
cells that deliver neurotropic factor(s) to dependent neurons. Recent
demonstration of regulated NGF synthesis by smooth muscle and glia allows
study of neurotrophin synthesis, secretion and their regulation.
Cultured smooth muscle will be used to reveal the extrinsic factors
(leukokines, cytokines, peptide agonists, neurotransmitters), intrinsic
events (Ca2+, protooncogene activation, intracellular messengers) and
other forces regulating NGF synthesis. Levels of NGF protein will be
measured with a sensitive two-site ELISA. NGF mRNA's will be examined
via a combination of qualitative and semiquantitative analyses. NGF
secretion and its requirements will be examined and any role of the
receptor for NGF.

The goal of understanding the forces that regulate NGF delivery in
important because the amount of factor acquired by innervating neurons
regulates their survival, complexity and connectivity, even in the adult.
It is not yet clear what specific disorders or diseases reflect
disturbances in neurotrophic factors. However, Alzheimer's disease, and
perhaps related senile dementias, are hypothesized to involve loss of
NGF-dependent neurons of the basal forebrain. NGF deficiencies are
thought to cause or contribute to the diabetic neuropathies. Bladder
hyperactivity following outlet obstruction involves anomalous growth of
innervating neurons and alterations in reflex function mediated by NGF.
An anomalous hyperinnervation of the hypertrophied vascular smooth muscle
in hypertension is also hypothesized to derive from an increased NGF
production. Knowledge of the cellular biology of neurotrophin production
and delivery will open new avenues for the treatment or prevention of
these prevalent and serious clinical problems.
StatusFinished
Effective start/end date1/1/0112/31/94

ASJC

  • Clinical Neurology
  • Neurology
  • Molecular Biology
  • Anatomy