Role of Selective Autophagy in Organismal Health

项目摘要 自噬是一种细胞内稳态过程，在衰老和与年龄相关的疾病中具有重要作用。期间 自噬，胞质物质或货物被隔离到称为自噬体的自噬囊泡中， 随后的溶酶体降解;然而，特定类型的turover 货物，例如，蛋白质聚集体或线粒体，统称为选择性自噬， 对细胞蛋白质稳定和有机体健康的影响仍然是难以捉摸的。 我们和其他人最近发现了第一个被鉴定的自噬货物受体在细胞内的保守作用。 后生动物，p62/SQSTM 1在介导蛋白质稳态和自噬依赖的生物体益处中的作用 方式特别是，我们发现p62在短寿命线虫C. elegans就足够了 诱导自噬，延长寿命和健康寿命，并主要在 神经元此外，p62是选择性地需要的兴奋性热休克的有益效果，保守的热休克， 长寿方案，我们以前显示诱导自噬。总的来说，这些研究表明， 假设p62在诱导组织特异性、选择性自噬以促进 有机体的好处这是一个新的概念，因为自噬受体传统上被视为因子 促进货物封存，而不是成为这种复杂的多步骤周转过程的积极诱导物。 我们建议通过使用C来解决这个假设。elegans研究分子机制， 通过p62或直接p62过表达的激素热休克自主调节自噬细胞， 通过细胞非自主效应改善生物体健康。具体而言，在目标1中，我们将使用遗传 测试激素热休克如何参与p62调节自噬的方法，特别是在神经元中。在 目的2：探讨p62诱导细胞凋亡的细胞自主和细胞非自主机制， 自噬和提高健身。最后，在目标3中，我们将使用遗传和生物化学方法来识别 新的p62相关的货物和p62样受体从事激素热休克。这些研究意义重大 因为它们将推进我们对选择性自噬如何促进生物体健康的认识。 这些研究是创新的，因为它们使用了技术和模型的强大组合， 研究自噬领域的新调控概念，即自噬受体足以 潜在地通过细胞非自主机制诱导有益自噬。因为自噬对于 在许多人类年龄相关疾病中的作用，了解自噬的调节和保守的 自噬影响多细胞生物衰老的机制，如C。秀丽线虫很可能提供 与衰老相关的新的重要见解，这也可能有助于开发与年龄有关的疾病的治疗方法。

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.