A major challenge encountered in the rehabilitation of patients with demyelinating disorders is posed by inefficient remyelination. The ability to stimulate Schwann cells (SC) and to augment remyelination would have a great impact the degree of functional recovery in these conditions. The neu gene encodes a tyrosine kinase growth factor receptor, termed p185. Previous studies suggested that p185 plays an important role in SC proliferation and differentiation. Several putative ligands for p185 have been described; two have been molecularly cloned, neu differentiation factor (NDF) and Heregulin. NDF is very similar to or identical to glial growth factor, among the most potent SC mitogens. The training program will provide the candidate with a comprehensive background in neurobiology and immunology through graduate-level coursework. The candidate also will develop expertise in the medical management and neurorehabilitation of patients with central and peripheral demyelinating diseases. The scientific goals are to characterize the expression of p185 ligands in nervous system and to define the biologic function of neu in SC. In Phase I, the developmental expression pattern and cellular specificity of p185 ligands in rat nervous system will be determined. Expression in a several pathological conditions will be characterized, including Wallerian degeneration following experimental allergic encephalomyelitis, peripheral demyelination caused by experimental allergic neuritis, and selected human peripheral nerve conditions associated with SC proliferation. In Phase II, the function of p185 in SC will examined using cultured rat SC, including effects on cell proliferation, morphology, and myelin gene expression. The intermolecular interactions of p185 in the SC membrane will be characterized. These studies will delineate the expression and source of p185 ligands in the nervous systems, begin to define the mechanisms regulating their expression, and clarify their function in SC. These studies should provide valuable insights into potential approaches to enhancing remyelination and thus improving the rehabilitation potential of demyelinating diseases. This program should provide the candidate with a unique combination of expertise in the neurologic, rehabilitative, and scientific aspects of demyelinating diseases.
Showing the most recent 10 out of 16 publications
