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.

项目总结 自噬是一种细胞内稳态过程，涉及细胞成分的自我消化。这个 自噬的底物被包裹在双层自噬小体中，这些自噬小体与溶酶体融合在一起 退化。自噬对于维持细胞和组织的完整性是必不可少的，并与许多 疾病和状况。虽然自噬在降解细胞质成分方面已经得到了广泛的研究，但其 人们对降解核材料的作用知之甚少。我最近发现自噬会退化 核层对致癌压力的反应，如激活的癌基因和DNA损伤。这 自噬降解是通过核膜与细胞核中的自噬蛋白相互作用来实现的，而 随后的核到细胞质的运输，导致细胞质自噬小体和 溶酶体。这一发现是哺乳动物自噬降解细胞核的首批例证之一。 成分，这一过程被称为核自噬。第一个核基质的鉴定 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领域，具有探索新研究的巨大潜力 林荫道。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。在这项提议中，我的目标是回答关于核衬底的一个主要未解决的领域，即 可以通过自噬来降解。该应用程序有两个方向。首先，我建议研究一种染色质 以核自噬为靶点的重塑复合体。第二，我建议不偏不倚地认定小说 核自噬的底物，采用先进的定量蛋白质组学。我的广泛假设是， 自噬引起的核和染色质成分的降解调节了细胞核的动态平衡，这是 是细胞应激反应的中心机制。这项研究将开创一种新的研究方向 自噬领域，并可能提供对生物医学的几个交叉领域的见解。