Introduction: This proposal seeks a period of supervised scientific training to enable Stephen J. Kanes M.D., Ph.D. to develop into an independent physician-scientist. The candidate completed graduate training in both Medicine and Molecular and Cellular Pharmacology at SUNY-Stony Brook followed by post-graduate clinical and research training at Yale University. During the proposed period of additional training, the candidate plans to develop the necessary skills to use animal models to investigate the neurobiology, pharmacology and genetics underlying inbred mouse strain differences in olfactory abilities and olfactoryguided behaviors. Background: Schizophrenia patients and their first-degree relatives have decreased olfactory detection threshold, identification, discrimination and memory. These are accompanied by specific neuropathological findings in the olfactory epithelium and bulb. Because both patients and unaffected relatives share these abnormalities, it is likely that the olfactory deficit is under genetic control and that this deficit may share some genetic risk factors with schizophrenia. Identifying these genes may provide important insights into the causes of schizophrenia itself. Inbred mice provide the ideal model system to begin exploring the genetic underpinnings of variation in olfactory structure and function. Research Project: The experiments proposed will examine the differences among 10 inbred mouse strains in olfactory-guided behaviors, olfactory bulb anatomy and the role of dopaminergic neurotransmission on olfaction. This battery will then be used in the evaluation of olfactory-guided behavior and olfactory bulb structure in D1, D2, D3 and D4 dopamine receptor knockout mice. Environment: The candidate will train in a structured environment that includes high-quality basic science and clinical research facilities. Senior mentoring will be geared towards facilitating methodological approaches to combine clinical observations with pre-clinical studies of olfaction. The primary training sites at the University of Pennsylvania will be in the Center for Neurobiology and Behavior under the supervision of Maja Bucan, Ph.D. and the Schizophrenia Research Center under the supervision of Raquel E. Gur, M.D., Ph.D. Research Career Development: In addition to the proposed research project, the candidate will participate in weekly lab meetings and attend seminars addressing scientific and ethical issues involved in animal and human research. A steering committee will meet with the candidate on a regular basis to supervise his progress. Data collected will serve as the basis for future quantitative trait locus analysis, targeted and random mutagenesis as well as anatomic and pharmacological investigation. These studies have the potential to provide new and important insights into the pathogenesis and treatment of schizophrenia. ? ?
