Role of Selective Autophagy in Organismal Health

选择性自噬在生物​​体健康中的作用

• 批准号: 10317840
• 负责人: Malene Hansen
• 金额: $ 51.78万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10317840
• 关键词: Address; Adult; Affect; Aging; Animal Model; Animals; Autophagocytosis; Autophagosome; Binding; Biochemical; Biological Assay; Biological Process; Caenorhabditis elegans; Cell physiology; Cells; Complex; Cytology; Data; Development; Disease; Distal; Elderly; Follow-Up Studies; Genes; Genetic; Health; Heat-Shock Response; Homologous Gene; Human; Instruction; Knowledge; Life; Longevity; Mammalian Cell; Mediating; Membrane; Mitochondria; Modeling; Molecular; Nematoda; Neurodegenerative Disorders; Neurons; Organism; Play; Population; Positioning Attribute; Process; Protein Isoforms; Proteins; Public Health; RNA Interference; Recycling; Regimen; Regulation; Reporter; Reporting; Research; Role; Signal Transduction; Site; Societies; Techniques; Testing; Time; Tissue Differentiation; Tissues; Vesicle; age related; cell type; combat; experimental study; fitness; genetic approach; healthspan; improved; in vivo; innovation; insight; mature animal; mutant; novel; novel therapeutic intervention; overexpression; promoter; protein aggregation; proteostasis; receptor; recruit; response; screening; stress granule; vesicular release

PROJECT SUMMARY Autophagy is a cellular, homeostatic process with important roles in aging and age-related diseases. During autophagy, cytosolic material or cargo is sequestered into autophagic vesicles called autophagosomes for subsequent lysosomal degradation; however, the underlying mechanisms for how the turover of specific types of cargo, e.g., protein aggregates or mitochondria, collectively referred to as selective autophagy, contributes to cellular proteostasis and organismal health remain elusive. We and others recently showed a conserved role for the first identified autophagy cargo receptor in metazoans, p62/SQSTM1 in mediating proteostasis and organismal benefits in an autophagy-dependent manner. In particular, we showed that p62 overexpression in the short-lived nematode C. elegans is sufficient to induce autophagy and extend life- and healthspan, and protect against protein aggregation predominantly in neurons. Moreover, p62 is selectively required for the beneficial effects of a hormetic heat shock, a conserved longevity regimen that we previously showed to induce autophagy. Collectively, these studies suggest the hypothesis that p62 plays an instructive role in inducing tissue-specific, selective autophagy to facilitate organismal benefits. This is a novel concept because autophagy receptors are traditionally viewed as factors facilitating cargo sequestration, rather than being active inducers of this complex, multi-step turnover process. We propose to address this hypothesis by using C. elegans to investigate the molecular mechanisms by which a hormetic heat shock via p62 or direct p62 overexpression regulate autophagy cell autonomously and improve organismal health via cell non-autonomous effects. Specifically, in Aim 1, we will use genetic approaches to test how a hormetic heat shock engages p62 to regulate autophagy especially in neurons. In Aim 2, we will investigate the cell-autonomous and cell non-autonomous mechanisms by which p62 induce autophagy and improve fitness. Finally, in Aim 3, we will use genetic and biochemical approaches to identify new p62-relevant cargo and p62-like receptors engaged by hormetic heat shock. These studies are significant because they will advance our knowledge of how selective autophagy contributes to organismal healthspan. These studies are innovative because they use a powerful combination of techniques and models to investigate the novel regulatory concept in the autophagy field that an autophagy receptor is sufficient to induce beneficial autophagy, potentially via cell non-autonomous mechanisms. Since autophagy plays critical roles in many human age-related disorders, 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 relevant to aging, which also may help develop treatments for age-related diseases.

项目摘要 自噬是一种细胞，稳态过程，在衰老和与年龄有关的疾病中起重要作用。期间 自噬，胞质材料或货物被隔离为称为自噬体的自噬囊泡，用于 随后的溶酶体降解；但是，针对特定类型的Turover的基本机制 货物，例如蛋白质聚集体或线粒体统称为选择性自噬，有助于 对于细胞蛋白质抑制和生物健康仍然难以捉摸。 最近，我们和其他人最近在首次确定的自噬货物受体中表现出保守的作用 自噬依赖性的蛋白质和生物益处中的p62/sqstm1，p62/sqstm1 方式。特别是，我们表明短寿命线虫中的p62过表达秀丽隐杆线已足够 诱导自噬并延长寿命和健康状态，并主要防止蛋白质聚集 神经元。此外，p62有选择性地需要刺激性热冲击的有益效果，保守的 我们以前表明的寿命方案是诱导自噬的。这些研究共同表明 假设p62在诱导组织特异性，选择性自噬方面起着指导性的作用 有机好处。这是一个新颖的概念，因为传统上将自噬受体视为因素 促进货物隔离，而不是成为这种复杂的多步周转过程的主动诱导者。 我们建议通过使用秀丽隐杆线虫研究通过 通过p62或直接p62过表达的炎热热冲击自动调节自噬细胞，并且 通过细胞非自治作用改善生物体健康。具体来说，在AIM 1中，我们将使用遗传 测试炎热冲击如何使P62调节自噬，尤其是在神经元中的方法。在 AIM 2，我们将研究p62诱导的细胞自主和细胞非自主机制 自噬并改善健身。最后，在AIM 3中，我们将使用遗传和生化方法来识别 新型P62相关的货物和P62类样受体，受刺激性热冲击吸引。这些研究很重要 因为他们将促进我们对选择性自噬对有机体健康状况有何贡献的了解。 这些研究具有创新性，因为它们将技术和模型的强大组合用于 研究自噬领域中的新型调节概念，即自噬受体足以足以 诱导有益的自噬，可能通过细胞非自主机制。由于自噬扮演关键 在许多与人类年龄有关的疾病中的角色，了解自噬的调节和保守的调节 自噬会影响秀丽隐杆线虫等多细胞生物的衰老的机制可能会提供 与衰老相关的新重要见解，这也可能有助于开发与年龄相关疾病的治疗方法。