Autophagy degradation of nuclear and chromatin constituents

核和染色质成分的自噬降解

• 批准号: 10026756
• 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/10026756
• 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.

项目概要 自噬是一种细胞稳态过程，涉及细胞成分的自我消化。这 自噬的底物被封闭在双膜自噬体中，该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至关重要，并且与许多 疾病和状况。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解 核纤层响应致瘤应激，例如激活的癌基因和 DNA 损伤。这 自噬降解是通过核纤层与细胞核中自噬蛋白的相互作用来实现的， 随后从细胞核到细胞质的转运，导致细胞质自噬体的降解 溶酶体。这一发现是哺乳动物自噬降解核的最早例证之一。 成分，这个过程称为核自噬。第一个核底物的鉴定 自噬促使我进一步研究哺乳动物自噬的核视角。 核自噬是一个新兴的新领域，具有探索新研究的巨大潜力 途径。我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。在本提案中，我的目的是回答有关核基质的一个主要未解决领域， 可被自噬降解。该应用程序有两个方向。首先，我建议研究染色质 核自噬靶向的重塑复合物。其次，我建议公正地识别小说 采用先进的定量蛋白质组学来研究核自噬的底物。我的广泛假设是 自噬对细胞核和染色质成分的降解介导细胞核的稳态，这 是细胞应激反应的核心机制。这项研究将开创一个新的研究方向 自噬领域，并可能为生物医学的几个交叉领域提供见解。