Calcium channels as novel therapeutic targets for Huntingtons Disease

项目描述（由申请人提供）：该项目的广泛、长期目标是验证CaV1.3电压门控钙（Ca2+）通道和TRPC1储存操作的Ca2+通道作为治疗亨廷顿病的新治疗靶点。亨廷顿氏病（HD）是一种常染色体显性致死性神经退行性疾病，由亨廷顿蛋白（Htt）氨基末端的聚谷氨酰胺重复序列（polyQ）扩增引起。纹状体中棘神经元（MSN）在HD中优先受到影响。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，也没有开发出改善疾病的疗法。紊乱的Ca2+信号被认为在HD发病机制中起关键作用。电压门控（VGCCs）和存储操作（SOC） Ca2+通道是神经元Ca2+信号的重要调节因子，最近的证据表明这些通道在HD中具有潜在的重要性。我的建议是：1。以YAC128 HD小鼠皮质神经元和纹状体神经元共培养，建立HD毒性体外生理检测方法。2. 通过遗传学方法验证CaV1.3 l型电压门控Ca2+通道作为HD治疗的潜在靶点。3. 验证TRPC1储存操作的Ca2+通道作为HD治疗的潜在靶点在体外和体内使用遗传学方法。4. 在细胞培养和YAC128 HD小鼠模型全动物实验中，评价CaV1.3 VGCC和trpc1支持的SOC通道药理学抑制剂作为HD治疗的潜在药物。验证CaV1.3 VGCC和TRPC1 SOC通道作为HD的新治疗靶点，将为开发新的治疗HD的药物创造机会。

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.