Calcium channels as novel therapeutic targets for Huntingtons Disease

描述(由申请人提供)：该项目广泛的长期目标是验证CaV1.3电压门控钙通道和TRPC1存储操作的钙通道作为治疗亨廷顿病的新治疗目标。亨廷顿病(HD)是一种常染色体显性遗传性致死性神经退行性疾病，由亨廷顿蛋白(Htt)氨基末端多聚谷氨酰胺重复序列(PolyQ)扩增引起。纹状体中棘神经元(MSN)优先受累于HD。突变的Htt具有许多毒性功能，但HD病理的确切原因尚不清楚，也没有开发出疾病修正疗法。错乱的钙信号被认为在HD的发病机制中起着关键作用。电压门控(VGCC)和存储操作(SOC)钙通道是神经元钙信号的重要调节者，最近的证据表明这些通道在HD中具有潜在的重要性。我建议：1.通过建立YAC128 HD小鼠皮质和纹状体神经元的共培养体系，建立HD毒性的生理学体外检测方法。2.用遗传学方法验证CaV1.3型L型电压门控性钙通道作为HD治疗的潜在靶点。3.用遗传学方法验证TRPC1库操作的钙通道在体外和体内作为HD治疗的潜在靶点。4.在YAC128 HD小鼠模型的细胞培养和全动物实验中，评价CaV1.3、VGCC和TRPC1支持的SOC通道的药理抑制剂作为治疗HD的潜在药物。CaV1.3 VGCC和TRPC1 SOC通道被确认为HD的新治疗靶点将为开发治疗HD的新治疗剂创造机会。

DESCRIPTION (provided by applicant): 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.