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Role of ASK1 for GAPDH-Siah binding and GAPDH-Siah stress-signaling in HD

ASK1 在 HD 中 GAPDH-Siah 结合和 GAPDH-Siah 应激信号传导中的作用

基本信息

批准号：
8063387
负责人：
Carlos Alberto Tristan
金额：
$ 4.18万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-27 至 2013-12-26
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8063387
关键词：
Address Affect Apoptosis Binding Binding Proteins Cell Death Cell Nucleus Cells Cellular Stress Response Cessation of life Complex Consensus Consensus Sequence Cysteine Data Disease Disease Progression Enzyme Gene Exposure to Fibroblasts Functional disorder Genetic Transcription Glyceraldehyde-3-Phosphate Dehydrogenases Grant Histones Homologous Gene Huntington Disease In Vitro Ischemia Knockout Mice Laboratories MAP3K5 gene Mediating Mentors Modeling Molecular Monitor Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Nuclear Localization Signal Nuclear Translocation Oxidative Stress Parkinson Disease Pathology Phosphorylation Phosphorylation Site Play Post-Translational Protein Processing Proteins RNA Interference Recombinant Proteins Recombinants Reporting Role Signal Pathway Signal Transduction Site Staging Stress Training base cytotoxicity human Huntingtin protein in vitro Assay in vitro testing mouse model mutant novel oxidation polyglutamine protein complex research study response sensor stressor therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Stress to cells can directly influence the expression, functional role, and the subcellular distribution of molecules within cells leading to cell death and/or dysfunction. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is one of these molecules modified by cell stressors and plays a critical role in cellular stress response. Posttranslational modifications of GAPDH induced by cell stressors allow it to function as a "sensor" and/or "relay" molecule that conveys stress signals into the nucleus by forming a complex with another protein called seven in absentia homolog 1 (Siah). In the nucleus this GAPDH-Siah complex causes various changes within the cell that have been associated with cell death and dysfunction. Activation of the GAPDH-Siah cascade demonstrated in Parkinson's disease (PD), and the nuclear colocalization of GAPDH and Huntingtin seen in Huntington's disease (HD), suggest that the GAPDH-Siah cascade may drive these neurodegenerative diseases. However, strong support for this idea is lacking. Our recent finds suggests that a third protein called apoptosis signal regulating kinase 1 (ASK1) might also be capable of triggering the GAPDH-Siah stress signaling cascade. Through the proposed training grant we will provide evidence to demonstrate that ASK1 activates the GAPDH-Siah stress signaling cascade in Huntington's disease by; 1) determining how ASK1 and GAPDH affect ASK1-Siah binding, 2) clarifying how ASK1 triggers GAPDH-Siah stress signaling and 3) directly examining the role of ASK1, GAPDH, and Siah in HD pathology. PUBLIC HEALTH RELEVANCE: Characterization of this novel stress-signaling cascade will help us understand the molecular mechanism underpining the progression of neurodegenerative diseases, such as HD. Characterization of this cascade in the context of neurodegeneration may help us identify potential therapeutic targets for the treatment of these diseases.

描述（由申请人提供）：对细胞的压力可以直接影响细胞内分子的表达、功能作用和亚细胞分布，导致细胞死亡和/或功能障碍。 3-磷酸甘油醛脱氢酶（GAPDH）是受细胞应激源修饰的分子之一，在细胞应激反应中发挥着关键作用。细胞应激源诱导的 GAPDH 翻译后修饰使其能够充当“传感器”和/或“中继”分子，通过与另一种称为缺席七同源物 1 (Siah) 的蛋白质形成复合物，将应激信号传递到细胞核中。在细胞核中，这种 GAPDH-Siah 复合物会引起细胞内的各种变化，这些变化与细胞死亡和功能障碍有关。帕金森病 (PD) 中显示的 GAPDH-Siah 级联的激活，以及亨廷顿病 (HD) 中观察到的 GAPDH 和亨廷顿蛋白的核共定位，表明 GAPDH-Siah 级联可能驱动这些神经退行性疾病。然而，这一想法缺乏强有力的支持。我们最近的发现表明，第三种称为凋亡信号调节激酶 1 (ASK1) 的蛋白质也可能能够触发 GAPDH-Siah 应激信号级联反应。通过拟议的培训拨款，我们将提供证据证明 ASK1 通过以下方式激活亨廷顿病中的 GAPDH-Siah 应激信号级联： 1) 确定 ASK1 和 GAPDH 如何影响 ASK1-Siah 结合，2) 阐明 ASK1 如何触发 GAPDH-Siah 应激信号传导，以及 3) 直接检查 ASK1、GAPDH 和 Siah 在 HD 病理学中的作用。公共健康相关性：这种新型应激信号级联的表征将帮助我们了解支持神经退行性疾病（例如 HD）进展的分子机制。在神经退行性变的背景下表征这一级联可能有助于我们确定治疗这些疾病的潜在治疗靶点。