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Calcium channels as novel therapeutic targets for Huntingtons Disease

钙通道作为亨廷顿病的新治疗靶点

基本信息

批准号：
8704830
负责人：
Ilya B Bezprozvanny
金额：
$ 34.43万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8704830
关键词：
Affect Animal Experiments Applications Grants Behavioral Assay Biological Assay Calcium Calcium Channel Caspase Cell Culture Techniques Cell Nucleus Clinical Trials Coculture Techniques Corpus striatum structure DARPP Dependovirus Dicer Enzyme Disease Foundations Future Genetic Genetic Crosses Glutamates Glutamine Grant Hereditary Disease Huntington Disease Image Impairment In Vitro Inherited Injection of therapeutic agent Inositol Isradipine Knockout Mice Laboratories Memantine Methods Molecular Motor Mus N-Methyl-D-Aspartate Receptors NMDA receptor antagonist Nerve Degeneration Neurodegenerative Disorders Neurons Nifedipine Oxidative Stress Pathogenesis Pathology Pathway interactions Physiological Play Preparation RNA Interference Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Synapses System Therapeutic Agents Toxic effect Transgenic Organisms Ubiquitin Validation Vertebral column Western Blotting Whole-Cell Recordings Work clinically relevant human Huntingtin protein in vitro Assay in vivo inhibitor/antagonist mitochondrial dysfunction mouse model multicatalytic endopeptidase complex mutant new therapeutic target novel novel therapeutics polyglutamine public health relevance pup receptor research study therapeutic development therapeutic target voltage

项目摘要

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.

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 存储操作的 Ca2+ 通道作为治疗亨廷顿病的新治疗靶点。亨廷顿病 (HD) 是一种常染色体显性遗传性致命性神经退行性疾病，由亨廷顿蛋白 (Htt) 蛋白氨基末端的聚谷氨酰胺重复序列 (polyQ) 扩增引起。纹状体中型多棘神经元 (MSN) 在 HD 中优先受到影响。突变体 Htt 具有多种毒性功能，但 HD 病理学的确切原因仍不清楚，并且尚未开发出缓解疾病的疗法。紊乱的 Ca2+ 信号传导被认为在 HD 发病机制中发挥着关键作用。电压门控 (VGCC) 和存储操作 (SOC) Ca2+ 通道是神经元 Ca2+ 信号传导的重要调节器，最近的证据表明这些通道在 HD 中具有潜在重要性。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物，开发 HD 毒性的体外生理测定法。 2. 利用遗传方法验证CaV1.3 L型电压门控Ca2+通道作为体外和体内HD治疗的潜在靶点。 3. 使用遗传方法验证 TRPC1 库操纵的 Ca2+ 通道作为体外和体内 HD 治疗的潜在靶点。 4. 使用 YAC128 HD 小鼠模型，在细胞培养和整体动物实验中评估 CaV1.3 VGCC 和 TRPC1 支持的 SOC 通道的药理学抑制剂作为 HD 治疗的潜在治疗剂。 CaV1.3 VGCC 和 TRPC1 SOC 通道作为 HD 新治疗靶点的验证将为开发新的 HD 治疗药物创造机会。