Regulation of the Autophagy Pathway with Age and in Long-lived Animals

长寿动物中自噬途径随年龄的调节

• 批准号: 10392270
• 负责人: Malene Hansen
• 金额: $ 60.28万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 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 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392270
• 关键词: Affect; Age; Aging; Animals; Autophagocytosis; Autophagosome; Auxins; Biochemical; Biochemical Genetics; Biological Assay; Biological Process; Caenorhabditis elegans; Cell Aging; Cell physiology; Cells; Complex; Cytology; Development; Disease; Disease model; Distal; Drug Screening; Elderly; Ensure; Fluorescence; Funding; Genes; Genetic; Health; Individual; Knowledge; Laboratories; Lead; Link; Lipids; Longevity; Lysosomes; Mammalian Cell; Measures; Membrane; Methods; Modeling; Molecular; Nematoda; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organism; Pathway interactions; Peptide Hydrolases; Persons; Pharmacology; Phenotype; Play; Population; Positioning Attribute; Process; Protein Secretion; Proteomics; Public Health; Publishing; Recycling; Regulation; Reporter; Research; Role; Societies; Techniques; Testing; Therapeutic; Time; Tissues; Vesicle; WD Repeat; Work; age related; combat; experimental study; fitness; gene function; human disease; in vivo; innovation; insight; lead candidate; mutant; novel; overexpression; protein degradation; receptor; small molecule; Affect; Age; Aging; Animals; Autophagocytosis; Autophagosome; Auxins; Biochemical; Biochemical Genetics; Biological Assay; Biological Process; Caenorhabditis elegans; Cell Aging; Cell physiology; Cells; Complex; Cytology; Development; Disease; Disease model; Distal; Drug Screening; Elderly; Ensure; Fluorescence; Funding; Genes; Genetic; Health; Individual; Knowledge; Laboratories; Lead; Link; Lipids; Longevity; Lysosomes; Mammalian Cell; Measures; Membrane; Methods; Modeling; Molecular; Nematoda; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Organism; Pathway interactions; Peptide Hydrolases; Persons; Pharmacology; Phenotype; Play; Population; Positioning Attribute; Process; Protein Secretion; Proteomics; Public Health; Publishing; Recycling; Regulation; Reporter; Research; Role; Societies; Techniques; Testing; Therapeutic; Time; Tissues; Vesicle; WD Repeat; Work; age related; combat; experimental study; fitness; gene function; human disease; in vivo; innovation; insight; lead candidate; mutant; novel; overexpression; protein degradation; receptor; small molecule

PROJECT SUMMARY Macroautophagy (referred to as autophagy) is a major cellular recycling process by which cytosolic material is sequestered into double-membrane vesicles or autophagosomes (i.e., early steps of autophagy), which subsequently fuse with lysosomes to ensure cargo degradation (i.e., late steps of autophagy). This complex, multi-step process plays key roles in organismal development and age-related diseases, and numerous direct links exist between autophagy and aging, including that multiple conserved longevity paradigms require autophagy genes for their lifespan extension; the current paradigm suggest that such long-lived animals induce autophagic turnover in a beneficial manner, yet the underlying mechanisms remain elusive. Our research in the previous funding cycle has provided a deeper understanding of the relationship between autophagy and aging in the nematode C. elegans. First, our work using cytological markers has indicated an age-related decline in late-steps of autophagy with variable trajectories in different tissues. Moreover, we have observed a differential regulation of autophagy in long-lived mutants in a tissue-specific fashion. Second, we have discovered unexpected longevity roles for specific autophagy genes in C. elegans neurons, indicating possibly non-canonical functions different from lysosomal degradation, an emerging concept in the autophagy research field which has yet to be investigated in the context of aging. Finally, we have conducted unbiased genetic and biochemical screens to identify new candidate autophagy regulators and receptors, and together with our collaborators identified a small compound that increase autophagy in both mammalian cells and in C. elegans and extends lifespan. Our prior studies provide us with new and specific hypotheses that we aim to test in depth in this renewal. Specifically, we will use a powerful combination of genetic and biochemical approaches to ask if fusion- and/or lysosomal degradation is a limiting step of the autophagy process in relation to organismal aging and longevity (Aim 1); we will ask if neuronal autophagy genes affect aging by cell non-autonomous means (Aim 2); and, finally, we will ask if new candidate autophagy receptors and autophagy-modulating molecules possess roles in longevity and in disease models (Aim 3). Autophagy plays critical roles in many disorders, including age-linked diseases 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 and may also help develop treatments for such age-related diseases, including neurodegenerative disorders.

项目摘要 大噬菌（称为自噬）是一个主要的细胞回收过程，胞质材料是 被隔离为双膜囊泡或自噬体（即自噬的早期步骤）， 随后与溶酶体融合以确保货物降解（即自噬的后期步骤）。这个复合物， 多步骤过程在有机体发育和与年龄有关的疾病中起关键作用，并且许多直接的直接作用 自噬与衰老之间存在联系，包括多个保守的寿命范式需要 自噬基因的寿命扩展；当前的范式表明如此长寿命的动物诱导 自噬以有益的方式进行自噬，但基本机制仍然难以捉摸。 我们在上一个资金周期中的研究为这种关系提供了更深入的了解 在线虫秀丽隐杆线虫中的自噬和衰老之间。首先，我们使用细胞学标记的工作具有 表明自噬的后台阶与不同组织中的轨迹变化相关。 此外，我们已经观察到在组织特异性的长寿命突变体中自噬的差异调节 时尚。其次，我们发现了秀丽隐杆线虫中特定自噬基因的意外寿命角色 神经元，表明可能非典型的功能与溶酶体降解不同， 自噬研究领域的概念尚未在衰老的背景下进行研究。最后，我们 已经进行了公正的遗传和生化筛选，以识别新的候选自噬调节剂和 受体，以及我们的合作者确定了一种小型化合物，可以增加两者的自噬 哺乳动物细胞和秀丽隐杆线虫中，并延长了寿命。 我们先前的研究为我们提供了新的和特定的假设，我们旨在在此续签中进行深入测试。 具体而言，我们将使用遗传和生化方法的强大组合来询问融合和/或是否融合 溶酶体降解是与生物衰老有关的自噬过程的限制步骤 （目标1）;我们将询问神经元自噬性基因是否会通过非自治手段影响衰老（AIM 2）；和， 最后，我们将询问新的候选自噬受体和自噬调节分子是否具有作用 在寿命和疾病模型中（目标3）。 自噬在许多疾病中起关键作用，包括与神经变性等年龄关联疾病。 了解自噬的调节和自噬影响衰老的保守机制 诸如秀丽隐杆线虫之类的多细胞生物不仅可以为衰老提供新的重要见解 还有助于开发有关此类与年龄相关疾病的治疗方法，包括神经退行性疾病。