Research

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 neurotrophinsthat interact with two distinct receptor types (Fig A).Alteredfunction of neurotrophins may be important in Alzheimer's, Parkinson's,or other neurological diseases. Dr. Neet's lab has used a varietyof biochemical, immunological, cytochemical, and spectroscopictechniques to quantitate the interaction of NGF with the two membranereceptors, determine the fate of NGF and/or its receptor insidethe cell, and study the cellular signals involved in cellularresponse of differentiation, proliferation, and apoptosis.

Enormous growth hasoccurred in neurotrophin research in recent years and the medicalimportance of this area has been recognized . The family of neurotrophins(BDNF, NT3, NT4/5) related to NGF are known to interact with thefamily of protein tyrosine kinase Trk receptors and the apoptosis-relatedcommon neurotrophin receptor, p75NTR, to provide important inputinto neuronal development in the embryo and to provide signalsfor maintenance of survival of neurons in aging and degenerativeneurological disorders. The potential has been raised for neurotrophinagonists, neurotrophin antagonists, inhibitors of the neurotrophinsignaling pathway, or inducers/repressors of neurotrophins tobe used in the treatment of Alzheimer's disease, Parkinson's disease,spinal cord defects, or simple aging. However, the level of understandingof basic molecular mechanisms of the neurotrophin/receptor familyis not yet sufficient to support this level of clinical optimism.We have been involved in studies of the nature of ligand-receptorinteractions with the overall objective of determining quantitativeaspects of protein-protein dynamics and signal transduction atthe molecular level with neurotrophins. The current work willprovide the basic molecular ground work and novel lead compoundsfor rational clinical treatment of neurological disorders. Thegoal is to be able to design neurotrophins that have cellular,receptor, and signaling specificity in order to be able to stimulatethe desired neuronal response at the correct target site to treata neurodegenerative disorder. Our approaches are complementaryto structural determinations from x-ray crystallography of NGFand NGF-receptor complexes, since we are studying the dynamicsof the process and creating novel reagents. No ligand-receptorsystem is yet understood at a sufficiently detailed quantitative,dynamic, and molecular level.