Suppression of the heat shock response in aging and neurodegeneration

抑制衰老和神经退行性疾病中的热休克反应

• 批准号: 7512138
• 负责人: Michael Y Sherman
• 金额: $ 24.38万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7512138
• 关键词: Acute; Address; Age; Aging; Animal Diseases; Caenorhabditis elegans; Cell Aging; Cell model; Cells; Complement; Condition; Data; Defect; Disease; Down-Regulation; Event; Feedback; Figs - dietary; Future; Genetic Transcription; Goals; Heat-Shock Response; Huntington Disease; Late-Onset Disorder; Lead; Mammalian Cell; Mediating; Modeling; Molecular Chaperones; Nerve Degeneration; Neurodegenerative Disorders; Organism; Parkinson Disease; Pathway interactions; Peptide Signal Sequences; Play; Protein Kinase; Proteins; Research; Role; Signal Pathway; Signal Transduction; Stress; System; TP53 gene; Testing; Toxic effect; Work; age related; aged; chaperone machinery; genetic inhibitor; heat shock transcription factor; human Huntingtin protein; improved; late disease onset; mouse model; mutant; polypeptide; prevent; protein misfolding; response; senescence

DESCRIPTION (provided by applicant): Several protective mechanisms have evolved in cells to handle accumulation of misfolded or mutant polypeptides. For example, molecular chaperones specifically serve to prevent aggregation and promote refolding of abnormal polypeptides. In conditions of acute accumulation of abnormal proteins when the demand for chaperones increases, a heat shock transcription factor, Hsf1, gets activated and promotes transcription of molecular chaperones. However, surprisingly, in many neurodegenerative disorders, including Huntington's (HD) or Parkinson's (PD) diseases, in spite of a build-up of abnormal pathological polypeptides, the levels of chaperones are reduced and induction of chaperones in response to stress is suppressed. Such suppression of the chaperone induction can reduce the ability of cells to handle misfolded pathological proteins, which would stimulate a positive feedback loop promoting toxicity and neurodegeneration. The heat shock response (HSR) is also strongly downregulated in aged organisms and senescent cells. This age-mediated suppression reduces the efficacy of the chaperone system, which could contribute to neurodegeneration in the late-onset disorders. We have found that signaling modules, including the p53-p21 signaling pathway and the protein kinase Cdk5 mediate suppression of the heat shock response in senescent cells. The goal of this proposal is to understand the sequence of signaling events that lead to suppression of the HSR in the cellular and C.elegans models of aging and neurodegeneration. Specifically, we will (1) establish the role of p53 in suppression of the HSR in cellular models of HD; (2) establish the role of Cdk5 in suppression of the HSR in cell senescence and cellular models of HD, and (3) establish the role of the p53 pathway and Cdk5 in suppression of the HSR in C.elegans models of aging and HD. This research will also address whether inhibition of Cdk5 can enhance the HSR and improve viability in aging and HD models. Many neurodegenerative disorders associated with aging are caused by accumulation of abnormal proteins. A special machinery of molecular chaperones has evolved to prevent aggregation and promote refolding and degradation of these abnormal species. The chaperone machinery however is downregulated in aging and disease, and this work will uncover signaling events that lead to suppression of the chaperone machinery.

描述（由申请人提供）：细胞中已进化出几种保护机制来处理错误折叠或突变多肽的积累。例如，分子伴侣专门用于防止异常多肽的聚集并促进其重折叠。在异常蛋白质急剧积累的情况下，当对伴侣的需求增加时，热休克转录因子 Hsf1 会被激活并促进分子伴侣的转录。然而，令人惊讶的是，在许多神经退行性疾病中，包括亨廷顿病（HD）或帕金森病（PD），尽管存在异常病理性多肽的积累，但伴侣蛋白的水平却降低，并且伴侣蛋白响应应激的诱导受到抑制。这种伴侣诱导的抑制可以降低细胞处理错误折叠的病理蛋白的能力，这将刺激促进毒性和神经变性的正反馈回路。热休克反应（HSR）在衰老生物体和衰老细胞中也被强烈下调。这种年龄介导的抑制降低了伴侣系统的功效，这可能导致迟发性疾病的神经退行性变。我们发现信号模块，包括 p53-p21 信号通路和蛋白激酶 Cdk5 介导抑制衰老细胞的热休克反应。该提案的目标是了解导致衰老和神经退行性细胞和线虫模型中 HSR 抑制的信号传导事件序列。具体来说，我们将 (1) 确定 p53 在 HD 细胞模型中抑制 HSR 中的作用； (2)确定Cdk5在细胞衰老和HD细胞模型中抑制HSR中的作用，以及(3)确定p53途径和Cdk5在抑制线虫衰老和HD模型中HSR中的作用。这项研究还将探讨抑制 Cdk5 是否可以增强 HSR 并提高衰老和 HD 模型的活力。许多与衰老相关的神经退行性疾病是由异常蛋白质的积累引起的。一种特殊的分子伴侣机制已经进化出来，可以防止这些异常物种的聚集并促进其重新折叠和降解。然而，伴侣机制在衰老和疾病中被下调，这项工作将揭示导致伴侣机制抑制的信号事件。