DESCRIPTION (provided by applicant): The candidate is a board-certified neuropathologist with advanced research background in developmental neurobiology. Throughout his training, he has applied genetically engineered mice to investigate the biology of c-kit ligand (stem cell factor) in hematopiesis and neurotrophic factors in programmed cell death in the nervous system. Since becoming a principal investigator, the applicant has applied his expertise in mouse genetics and human neuropathology to mentoring students and postdoctoral fellows. This award will protect the applicant from clinical and administrative responsibilities. It will also allows him to devote a greater amount of time to develop mouse models for protecting DA neurons and to mentoring new investigators in mouse pathobiology research. The formal mentoring plans sponsored by this award include: 1) Establish a campus-wide mouse pathobiology mentoring/training program that addresses the fundamental uses of genetically engineered mice (GEM); and 2) Establish a minicourse training program on the DAergic system using GEM as a model organism. The research plans proposed for this award are built on recent findings that TGF¿ and its downstream signaling kinase HIPK2 support the survival of midbrain DA neurons. Targeted deletion of TGF¿3 or HIPK2 leads to increased apoptosis and a significant loss of DA neurons in the period of programmed cell death during development. Intriguingly, our recent results show that both HIPK1 and HIPK2 are expressed in ventral midbrain during early stages in development. More importantly, simultaneous loss of TGF¿2 and TGF¿3 or HIPK1 and HIPK2 leads to similar phenotype with even more robust deficits in the early development of midbrain DA neurons. These results lead us to the hypothesis that TGF¿-HIPK signaling pathway provides robust trophic factor support that regulates neurogenesis, survival and maturation of midbrain DA neurons in a stage-dependent fashion. We propose several mouse models to test this hypothesis. Results from this study will provide the first evidence that different TGF¿ isoforms and its associated downstream signaling pathways work in concert to regulate various aspects of the development and maintenance of DA neurons during its entire life span. Our long-term goal is to use information from these mutants as platforms to identify therapeutic targets that can promote survival of DA neurons under neurodegenerative conditions. Parkinson's disease is the second most common neurodegenerative disease that affects more than 1.5 million patients in US. In this study, we propose to generate mouse mutants that are defective in TGF¿- HIPK2 signaling and to characterize how this pathway regulates survival and cell death in DA neurons. Our results will provide important insights to identifying novel therapeutic targets for Parkinson's disease.