Autophagy degradation of nuclear and chromatin constituents

核和染色质成分的自噬降解

• 批准号: 10408753
• 负责人: Zhixun Dou
• 金额: $ 42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408753
• 关键词: Area; Autophagocytosis; Autophagosome; Biology; Cell Nucleus; Cells; Cellular Stress; Chromatin; Chromatin Remodeling Factor; Cytoplasm; DNA Damage; Digestion; Disease; Eating; Goals; Homeostasis; Laboratories; Lysosomes; Mediating; Membrane; Nuclear; Nuclear Lamina; Oncogenes; Process; Proteins; Proteomics; Research; Role; Stress; Tissues; biological adaptation to stress; human disease; insight; novel; response; tumorigenic

PROJECT SUMMARY Autophagy is a cell homeostasis process that involves self-digestion of cellular components. The substrates of autophagy are enclosed in double-membraned autophagosomes that fuse with lysosomes for degradation. Autophagy is essential for maintaining cell and tissue integrity, and is implicated in a number of diseases and conditions. While autophagy has been widely studied in degrading cytoplasmic components, its role in degrading nuclear materials is poorly understood. I recently discovered that autophagy degrades nuclear lamina in response to tumorigenic stress, such as activated oncogenes and DNA damage. This autophagic degradation is through nuclear lamina interaction with autophagy proteins in the nucleus, and a subsequent nucleus-to-cytoplasm transport, leading to degradation by the cytoplasmic autophagosomes and lysosomes. This discovery was one of the first illustrations of mammalian autophagy degrading nuclear components, a process termed as nuclear autophagy. The identification of the first nuclear substrate of autophagy prompted me to further investigate nuclear perspectives of mammalian autophagy. Nuclear autophagy is an emerging new field with tremendous potential to explore new research avenues. A central goal of my laboratory is to study the biology of nuclear autophagy and its implication in diseases. In this proposal, I aim to answer a major unaddressed area regarding the nuclear substrates that can be degraded by autophagy. The application has two directions. First, I propose to investigate a chromatin remodeling complex that is targeted by nuclear autophagy. Second, I propose to unbiasedly identify novel substrates of nuclear autophagy, employing advanced quantitative proteomics. My broad hypothesis is that the degradation of nuclear and chromatin constituents by autophagy mediates homeostasis of the nucleus, which is a central mechanism of cell stress responses. This study will pioneer a new research direction in the autophagy field, and may offer insights into several intersecting areas of biomedicine.

项目摘要 自噬是一种涉及细胞成分自我消化的细胞内稳态过程。的 自噬的底物被包裹在双膜自噬体中，自噬体与溶酶体融合， 降解自噬对于维持细胞和组织的完整性是必不可少的，并且与许多细胞和组织的功能有关。 疾病和条件。虽然自噬在降解细胞质成分方面已被广泛研究，但其 人们对核材料降解的作用知之甚少。我最近发现自噬会降低 核纤层对致瘤应激的反应，如激活的癌基因和DNA损伤。这 自噬降解是通过核纤层与核中的自噬蛋白相互作用， 随后的核到细胞质转运，导致细胞质自噬体降解， 溶酶体这一发现是哺乳动物自噬降解细胞核蛋白的第一个例证之一。 这一过程被称为核自噬。第一核底物的鉴定 自噬促使我进一步研究哺乳动物自噬的核观点。 核自噬是一个新兴的新领域，具有巨大的探索新研究的潜力 大道。我的实验室的一个中心目标是研究核自噬的生物学及其在 疾病在这个建议中，我的目的是回答一个主要的未解决的领域，关于核基板， 可以被自噬作用降解。应用程序有两个方向。首先，我打算研究一种染色质， 核自噬靶向的重塑复合物。第二，我建议无偏见地认定小说 核自噬的底物，采用先进的定量蛋白质组学。我的假设是 细胞核和染色质成分的降解通过自噬介导细胞核的稳态， 是细胞应激反应的中心机制。本研究将为生物医学领域开辟一个新的研究方向， 自噬领域，并可能提供深入了解几个交叉领域的生物医学。