Role of sumoylation in aging

苏酰化在衰老中的作用

• 批准号: 9807523
• 负责人: Andrew Vaughn Samuelson
• 金额: $ 26.95万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807523
• 关键词: Adult; Affect; Age; Aging; Alzheimer' s Disease; Biological; Biological Models; Caenorhabditis elegans; Cell Lineage; Cell Nucleus; Cell physiology; Cells; Chromatin; Chromatin Remodeling Factor; Clinical; Complex; Deposition; Deterioration; Development; Disease; Down-Regulation; Drops; Enzymes; Event; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Heat-Shock Response; Histones; Human; Intervention; Late Onset Alzheimer Disease; Learning; Link; Longevity; Maintenance; Mitochondria; Modeling; Molecular; Molecular Chaperones; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Nuclear; Oxidative Stress; PRC1 Protein; Patients; Polycomb; Process; Proteins; Proteome; Resistance; Role; Single Nucleotide Polymorphism; Stem cells; Stress; Testing; Work; age related; biological adaptation to stress; chromatin remodeling; cohort; design; epigenome; healthy aging; heat shock transcription factor; improved; insight; isopeptidase; mature animal; normal aging; preservation; prevent; programs; protein misfolding; proteostasis; proteotoxicity; recruit; response; role model; transcription factor

Project Summary/Abstract: The mechanisms that maintain proper function and folding of the proteome (proteostasis) decline during normal aging, which facilitates the onset and progression of neurodegenerative protein misfolding diseases, including Alzheimer's Disease. The functional integrity of the proteome is safeguarded from stress through the combined action of a cohort of transcription factors, each primed to respond to specific forms of proteotoxic stress. During aging, these responses decline and ultimately precipitate a collapse of proteostasis. C. elegans is an excellent model to study the molecular mechanisms involved in this complex process: in particular, the inducibility of the heat shock response, mitochondrial unfolded protein response, ER unfolded protein response, and the oxidative stress response all rapidly decline concurrent with early signs of declining proteostasis. Why the inducibility in response to diverse forms of proteotoxic stress declines, however, is poorly understood, but coincides with the formation of repressive chromatin marks at stress loci. We have identified inappropriate sumoylation during aging as a potential mechanism to explain loss of stress response inducibility. This project will explore how changes in sumoylation during aging alter the epigenome, inducibility of stress responses, and maintenance of proteostasis. The objectives of this proposal are to identify nuclear changes in sumoylation during aging and gain mechanistic insight into how altered sumoylation intersects with changes in chromatin, inducibility of stress response, and the consequence on proteostasis and longevity. Our central hypothesis is that the inducibility of stress response programs maintaining proteostasis declines because increased sumoylation results in aberrant recruitment of chromatin remodeling complexes to stress loci. We have discovered an age-associated increase in sumoylation of a transcriptional regulator of proteostasis, and blocking sumoylation prevents the downregulation of stress response in adult animals. Conversely, preventing deSUMOylation shortens lifespan and represses gene expression. Notably, expression can be rescued by inactivation of chromatin modifying enzymes, consistent with the notion that age-related changes in sumoylation are linked to the activity of chromatin remodeling complexes. Aim 1 is centered on deciphering whether increasing sumoylation during early C. elegans aging, which coincides with the precipitous drop in stress response, is causative in declining proteostasis and longevity. Aim 2 centers on a mechanistic analysis to identify interconnections between sumoylation, chromatin remodeling complexes, and changes in chromatin at stress loci. The focus of Aim 3 is on the transcription factors themselves that directly regulate components of the proteostatic network and the functional consequence of their sumoylation during aging. Many of the causative factors of neurodegenerative diseases are sumoylated and mutations in core components of the sumoylation machinery are found in AD patients. Thus, elucidating the intersection between sumoylation, chromatin, and the proteostatic network may have implications for the treatment of neurodegenerative disease and efforts to improve healthy aging.

项目摘要/摘要： 在正常情况下保持适当功能和蛋白质组（蛋白质的折叠）的机制 衰老，促进神经退行性蛋白质错误折叠疾病的发作和进展，包括 阿尔茨海默氏病。蛋白质组的功能完整性通过合并的压力保护 一系列转录因子的作用，每个人都需要响应特定形式的蛋白质毒性应激。期间 衰老，这些反应会下降并最终导致蛋白质的崩溃。秀丽隐杆线虫是一个极好的 研究这一复杂过程涉及的分子机制的模型：特别是， 热休克反应，线粒体展开的蛋白质反应，ER展开的蛋白质反应和氧化 压力反应均与早期蛋白质的早期迹象同时迅速下降。为什么在 然而，对各种形式的蛋白质毒性胁迫下降的反应知之甚少，但是与 应力基因座的抑制性染色质标记的形成。我们已经确定了衰老期间不合适的sumoylation 作为解释应力响应性丧失的潜在机制。该项目将探讨如何改变 在衰老期间的sumoylation中，应改变表观基因组，应力反应的诱导性和维持 蛋白毒酸。该提案的目标是确定衰老期间苏硫化的核变化 获取机械洞察力，了解改变的sumoylation如何与染色质变化，应力诱​​导性相交 反应以及对蛋白质和寿命的后果。我们的中心假设是 压力反应计划维持蛋白接种的情况下降，因为增加的sumoylation会导致异常 募集染色质重塑络合物以应力基因座。我们发现与年龄相关的增加 在蛋白毒酸群的转录调节剂和阻塞sumoylation的汇总调节器中，可防止 成年动物压力反应的下调。相反，防止desumoylation缩短了寿命 并抑制基因表达。值得注意的是，可以通过染色质修饰来挽救表达 酶，与与年龄相关的sumoylation变化的观念一致 染色质重塑络合物。 AIM 1集中在解密是否在早期增加Sumoylation 秀丽隐杆线虫的衰老与压力反应的急剧下降相吻合，在下降中是一种原因 蛋白质和寿命。目标2以机械分析为中心，以识别 Sumoylation，染色质重塑复合物以及应力基因座染色质的变化。 AIM 3的重点是 关于转录因素本身，直接调节蛋白抑制网络的组成部分和 它们在衰老过程中的功能后果。神经退行性的许多因果因素 疾病是Sumoy的，在AD中发现了Sumoylation机械核心成分的突变 患者。因此，阐明sumoylation，染色质和蛋白质静态网络之间的相交 对治疗神经退行性疾病的治疗和改善健康衰老的努力有影响。