Neurotrophic factors play a major role in development and maintenance of many types of neurons. The family of nerve growth factor (NGF) related neurotrophins (BDNF, NT-3, NT-4/5) interact with a low affinity neurotrophin receptor (p75NTR) and with the family of trk proto-oncogene receptor tyrosine kinases (Trk) to establish signaling within responsive peripheral neurons (sensory, sympathetic) and central neurons (cholinergic, dopaminergic). The overall hypothesis being tested in this proposal is that the initial interaction between NGF and its receptors involves a conformational change and receptor dimerization that leads to discrete intracellula signaling pathways that can be separately activated by appropriate NGF mutants. Such effects could lead to novel and highly specific therapeutic agents in neurological disorders.
The Specific Aims of this application that address this hypothesis are: to develop NGF mutants that independently signal for differentiation, growth arrest, apoptosis and survival; to determine the signaling pathways that distinguish these mutants; and to measure conformational changes upon interaction of NGF and the mutants with the TrkA-RED and of the four neurotrophins with the p75NTR-RED utilizing various fluorescence techniques. In general, these projects utilize purified protein components with physical biochemical techniques and PC12 cells for signaling analysis. All NGF mutants are purified and characterized for structural integrity. Molecular biological, immunochemical, spectroscopic, and chemical approaches will be utilized. The results expected here will help lay the foundation for the meaningful and rational design of therapeutic reagents derived from neurotrophin mutants that selectively stimulate signaling pathways and could eventually lead to novel treatments of Alzheimer's Disease, Parkinson's Disease, childhood neuroblastomas, and related neurological disorders. For example, NGF is now known to prevent atrophy 0 CNS neurons and to stimulate regeneration of sensory neurons in the spinal cord - our response-selective NGF mutants may be even more effective in ultimately treating such neurological disorders.
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