This is a resubmission of an application for a Clinical Investigator Development Award designed to provide the applicant with the research skills and experience in a fundamental science necessary to develop into an independent investigator on the interface of the basic and clinical sciences. Since the discovery of nerve growth factor almost 40 years ago, the number of substances identified with neuronotrophic properties, and our understanding of their activity has expanded enormously. Despite the widespread interest in these factors and the great effort undertaken to study them, there has been little progress in applying these factors clinically. In this project we propose animal models to characterize the neurotoxic effects of several important therapeutic agents. We will also use this model to investigate the ability of at least four different neuronotrophic factors to prevent and reverse toxic neuropathies in vivo. We have carefully selected a small fiber sensory neurotoxin (taxol), a large fiber sensory neurotoxin (cisplatin), a mixed motor and sensory neuropathy (vincristine) and two new unclassified neuropathies (ddI and ddC) to study. If successful, these studies will lay the groundwork for clinical trials which may extend the usefulness of several important anti- tumor agents for which neurotoxicity is the dose limiting toxicity. Of greater importance in the long run, these studies will initiate a clinically useful role for neuronotrophic factors.
