The broad, long-term objective of the project is to validate CaV1.3 voltage-gated calcium (Ca2+) channels and TRPC1 store-operated Ca2+ channels as novel therapeutic targets for treatment of Huntington's disease. Huntington's disease (HD) is an autosomal-dominant and fatal neurodegenerative disorder caused by polyglutamine repeat (polyQ) expansion in the amino-terminal of Huntingtin (Htt) protein. Striatal medium spiny neurons (MSN) are preferentially affected in HD. A number of toxic functions have been assigned to mutant Htt, but exact causes of HD pathology remain unknown and no disease-modifying therapy has been developed. Deranged Ca2+ signaling has been proposed to play a key role in HD pathogenesis. Voltage-gated (VGCCs) and store-operated (SOC) Ca2+ channels are important regulators of neuronal Ca2+ signaling, and recent evidence suggested potential importance of these channels in HD. I propose: 1. To develop the physiological in vitro assay for HD toxicity by establishing co-cultures from cortical and striatal neurons from YAC128 HD mice. 2. To validate the CaV1.3 L-type voltage-gated Ca2+ channel as potential target for HD treatment in vitro and in vivo using genetic methods. 3. To validate the TRPC1 store-operated Ca2+ channel as potential target for HD treatment in vitro and in vivo using genetic methods. 4. To evaluate pharmacological inhibitors of CaV1.3 VGCC and TRPC1-supported SOC channels as potential therapeutic agents for HD treatment in cell culture and whole animal experiments with YAC128 HD mouse model. Validation of CaV1.3 VGCC and TRPC1 SOC channels as novel therapeutic targets for HD will create an opportunity for developing novel therapeutic agents for cure of HD. PUBLIC HEALTH RELEVANCE: The proposed project will have direct and immediate relevance for public health. Huntington's disease (HD) is an incurable genetic disorder that causes enormous suffering. The experiments described in the grant are aimed at validating novel therapeutic targets for treatment of HD.