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：
8263938
负责人：
Ilya B Bezprozvanny
金额：
$ 34.74万
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/8263938
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. 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.

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商店经营的CA2+通道，作为治疗亨廷顿疾病的新型治疗靶标。亨廷顿氏病（HD）是由多谷氨酰胺重复（PolyQ）在亨廷顿蛋白（HTT）蛋白质氨基末端扩张引起的常染色体主导和致命的神经退行性疾病。纹状体培养基神经元（MSN）在HD中优先影响。许多有毒功能已分配给突变体HTT，但是HD病理学的确切原因尚不清楚，并且没有开发出疾病的治疗。已经提出了精神错乱的Ca2+信号传导在HD发病机理中起关键作用。电压门控（VGCC）和商店操作（SOC）CA2+通道是神经元CA2+信号传导的重要调节剂，最近的证据表明这些通道在HD中的潜在重要性。我建议：1。通过建立来自Yac128 HD小鼠皮质和纹状体神经元的共培养来开发HD毒性的生理体外测定。 2。验证Cav1.3 L型电压门控Ca2+通道作为使用遗传方法在体外和体内进行HD处理的潜在靶标。 3。使用遗传方法验证TRPC1存储的Ca2+通道作为体外和体内HD处理的潜在靶标。 4。评估CAV1.3 VGCC和TRPC1支持的SOC通道的药理抑制剂，作为细胞培养中HD治疗的潜在治疗剂，并使用YAC128 HD小鼠模型进行了整个动物实验。 CAV1.3 VGCC和TRPC1 SOC渠道作为HD的新治疗靶标的验证将为开发新型的HD治疗治疗剂创造机会。公共卫生相关性：拟议的项目将与公共卫生有直接的直接相关性。亨廷顿氏病（HD）是一种无法治愈的遗传疾病，会引起巨大的痛苦。赠款中描述的实验旨在验证用于治疗HD的新型治疗靶标。