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.

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