Regulation of the Autophagy Process in Organismal Aging

机体衰老过程中自噬过程的调节

• 批准号: 9177711
• 负责人: Malene Hansen
• 金额: $ 39.98万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177711
• 关键词: Adaptor Signaling Protein; Address; Adult; Affect; Age; Aging; Animal Model; Animals; Autophagocytosis; Behavioral Assay; Binding; Biochemical; Biological Assay; Biological Process; Caenorhabditis elegans; Candidate Disease Gene; Cell physiology; Complement; Complex; Coupled; Data; Development; Disease; Elderly; Genes; Genetic; Goals; Grant; Health; Human; Intestines; Knowledge; Laboratories; Life; Link; Longevity; Lysosomes; Mammalian Cell; Measures; Methods; Modeling; Molecular; Mus; Muscle; Nematoda; Nerve Degeneration; Neurons; Organism; Physiological; Play; Population; Positioning Attribute; Process; Proteins; Proteomics; Public Health; Publishing; RNA Interference; Recycling; Regulation; Regulator Genes; Reporter; Research; Rodent; Role; Signal Transduction; Societies; System; Techniques; Testing; Time; Tissues; Work; age related; base; fitness; in vivo; inhibition of autophagy; innovation; insight; mutant; normal aging; novel; overexpression; research study; screening

PROJECT SUMMARY Autophagy is a major cellular recycling process by which cytosolic cargo is sequestered and degraded in the lysosome. This multi-step process plays important roles in development, disease, and aging. Direct links between autophagy and aging exist in multiple conserved longevity paradigms; such long-lived animals are thought to induce autophagy in a beneficial manner, yet the underlying mechanisms remain elusive. Ours and others' research have firmly established links between autophagy and longevity in the nematode C. elegans by showing that autophagy genes are required for the long lifespan of all conserved longevity paradigms tested. Moreover, our unpublished results indicate that autophagy is functionally relevant for longevity in all major tissues of the long-lived C. elegans mutants we have analyzed so far, and autophagy generally appears induced in tissues of long-lived mutants, but declines over time in wild-type animals. We and others have also shown that several transcriptional and post-translational regulators of autophagy play roles in aging, suggesting that autophagy is subject to complex regulation over time. While collectively establishing a critical role for autophagy in multiple tissues of C. elegans, these studies did not address which tissue-specific functions autophagy may control that affect organismal healthspan. Moreover, it is unclear how autophagy is temporally and spatially regulated in long-lived mutants and during normal aging. The goal of this application is to address these gaps in knowledge by using a combination of genetic, biochemical and behavioral assays primarily in C. elegans, but also in mammalian systems. Specifically, in Aim 1, we will use quantitative PCR and targeted proteomics to characterize how the autophagy process is regulated during aging in C. elegans and murine tissues. Moreover, we will use SILAC-coupled proteomics to measure degradation rates of select autophagy cargos in C. elegans tissues. In Aim 2, we will analyze tissue-specific roles for autophagy in C. elegans healthspan, and analyze the effects on health- and lifespan of overexpressing key autophagy-regulatory genes in a temporal and spatial-controlled manner. Finally, in Aim 3, we will use genetic and biochemical screening approaches to search for new regulators of autophagy, including factors important for autophagic cargo recognition. Autophagy plays critical roles in many diseases, including age-related disorders such as neurodegeneration. Understanding the regulation of autophagy and the conserved mechanisms by which autophagy affect aging in multicellular organisms like C. elegans are likely to provide new important insights not only into aging but may also help develop treatments for such age-related diseases.

项目摘要 自噬是一种主要的细胞回收过程 溶酶体。这个多步骤过程在发育，疾病和衰老中起着重要作用。直接链接 自噬和衰老之间存在于多个保守的寿命范式中；如此长寿的动物是 被认为是以有益的方式诱导自噬的，但潜在的机制仍然难以捉摸。 我们和其他人的研究已经在线虫中牢固建立了自噬与寿命之间的联系 秀丽隐杆线虫通过证明所有保守寿命的长寿命需要自噬基因 测试范例。此外，我们未发表的结果表明自噬在功能上与 到目前为止，我们已经分析了长期寿命秀丽隐杆线虫突变体的所有主要组织的寿命，并且自噬 通常在长寿命突变体的组织中诱导，但在野生型动物中随着时间的流逝而下降。我们和 其他人还表明，自噬的几个转录和后翻译调节剂在 衰老，表明自噬会随着时间的流逝而受到复杂的调节。 这些研究共同在秀丽隐杆线虫的多个组织中建立了自噬的关键作用，但这些研究 没有解决自噬可能控制哪种组织特异性功能，从而影响有机体健康状况。 此外，目前尚不清楚自噬如何在长寿突变体中以及在空间上进行调节 正常衰老。此应用的目的是通过结合使用 遗传，生化和行为分析主要在秀丽隐杆线虫中，也是在哺乳动物系统中。 具体而言，在AIM 1中，我们将使用定量PCR和靶向蛋白质组学来表征自噬的方式 在秀丽隐杆线虫和鼠组织衰老期​​间，过程受到调节。此外，我们将使用Silac耦合 蛋白质组学测量秀丽隐杆线虫组织中精选自噬的降解速率。在AIM 2中，我们将 分析秀丽隐杆线虫健康范围内自噬的组织特异性作用，并分析对健康和健康的影响 过表达密钥自噬调节基因的寿命，以时间和空间控制的方式。 最后，在AIM 3中，我们将使用遗传和生化筛选方法来寻找新的调节剂 自噬，包括对自噬货物识别重要的因素。 自噬在许多疾病中起关键作用，包括与年龄有关的疾病，例如 神经变性。了解自噬的调节和保守机制 自噬影响秀丽隐杆线虫等多细胞生物的衰老可能会提供新的重要见解 不仅进入衰老，而且还可能有助于开发与年龄相关疾病的治疗方法。