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: 7668382
• 负责人: Michael Y Sherman
• 金额: $ 20.31万
• 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/7668382
• 关键词: Acute; Address; Age; Aging; Animal Diseases; Caenorhabditis elegans; Cell Aging; Cell Culture Techniques; Cell model; Cells; Complement; 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）：细胞中已经进化了几种保护机制，以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聚集并促进异常多肽的重折叠。在异常蛋白质急性积累时，当对伴侣的需求增加时，热休克转录因子HSF1，被激活并促进分子伴侣的转录。然而，令人惊讶的是，尽管在许多神经退行性疾病中，包括亨廷顿（HD）或帕金森氏症（PD）疾病，尽管存在异常的病理多肽，但抑制了伴侣的伴侣伴侣的伴侣水平，抑制了伴侣的伴侣诱导。这种抑制伴侣诱导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阳性反馈回路。在老化的生物和衰老细胞中，热休克反应（HSR）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，这可能导致晚期疾病的神经变性。我们发现，信号模块，包括p53-P21信号通路，蛋白激酶CDK5介导了衰老细胞中热休克反应的抑制。该提案的目的是了解导致衰老和神经变性的细胞模型中HSR抑制的信号传导事件的顺序。具体而言，我们将（1）确定p53在抑制HSR中的作用在HD的细胞模型中； （2）在HD的细胞衰老和细胞模型中确定CDK5在抑制HSR中的作用，（3）确定p53途径和CDK5在抑制HSR中的作用。这项研究还将解决CDK5的抑制是否可以增强HSR并提高衰老和HD模型的生存能力。与衰老相关的许多神经退行性疾病是由异常蛋白的积累引起的。分子伴侣的一种特殊机制已进化，以防止聚集并促进这些异常物种的再折叠和降解。然而，伴侣机械在衰老和疾病中被下调，这项工作将发现导致抑制伴侣机械的信号事件。