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Role of Selective Autophagy in Organismal Health

选择性自噬在生物体健康中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目总结