Nerve growth factor (NGF) is a neurotrophin that is important in development of sympathetic, sensory and central neurons. NGF is a member of a family of neurotrophins that interact with two distinct receptor types (Fig A). Altered function of neurotrophins may be important in Alzheimer's, Parkinson's, or other neurological diseases. Dr. Neet's lab has used a variety of biochemical, immunological, cytochemical, and spectroscopic techniques to quantitate the interaction of NGF with the two membrane receptors, determine the fate of NGF and/or its receptor inside the cell, and study the cellular signals involved in cellular response of differentiation, proliferation, and apoptosis.
Enormous growth has occurred in neurotrophin research in recent years and the medical importance of this area has been recognized. The family of neurotrophins(BDNF, NT3, NT4/5) related to NGF are known to interact with the family of protein tyrosine kinase Trk receptors and the apoptosis-related common neurotrophin receptor, p75NTR, to provide important input into neuronal development in the embryo and to provide signals for maintenance of survival of neurons in aging and degenerative neurological disorders. The potential has been raised for neurotrophin agonists, neurotrophin antagonists, inhibitors of the neurotrophin signaling pathway, or inducers/repressors of neurotrophins to be used in the treatment of Alzheimer's disease, Parkinson's disease, spinal cord defects, or simple aging. However, the level of understanding of basic molecular mechanisms of the neurotrophin/receptor family is not yet sufficient to support this level of clinical optimism. We have been involved in studies of the nature of ligand-receptor interactions with the overall objective of determining quantitative aspects of protein-protein dynamics and signal transduction at the molecular level with neurotrophins. The current work will provide the basic molecular ground work and novel lead compounds for rational clinical treatment of neurological disorders. The goal is to be able to design neurotrophins that have cellular, receptor, and signaling specificity in order to be able to stimulate the desired neuronal response at the correct target site to treat a neurodegenerative disorder. Our approaches are complementary to structural determinations from x-ray crystallography of NGFand NGF-receptor complexes, since we are studying the dynamics of the process and creating novel reagents. No ligand-receptor system is yet understood at a sufficiently detailed quantitative, dynamic, and molecular level.