Autophagy-mediated chromatin degeneration in aging and age-related diseases

衰老和年龄相关疾病中自噬介导的染色质变性

• 批准号: 9791148
• 负责人: Zhixun Dou
• 金额: $ 24.6万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791148
• 关键词: ADP Ribose Transferases; Address; Age; Aging; Area; Autophagocytosis; Caloric Restriction; Cell Aging; Cell Cycle Arrest; Cell Nucleus; Cells; Chromatin; Chromatin Remodeling Factor; Chronic; Cytoplasm; DNA; Deacetylase; Digestion; Disease; Down-Regulation; Event; Faculty; Family; Future; General Population; Genetic Transcription; Heterochromatin; Homeostasis; Human; Immune; Immune system; Infection; Infiltration; Inflammaging; Inflammation; Inflammatory; Intervention; Investigation; Knowledge; Lamin B1; Lamins; Link; Longevity; Lysosomes; Mass Spectrum Analysis; Mediating; Membrane; Mentors; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Nature; Nuclear; Nuclear Lamina; Oncogene Activation; Organism; Pathologic; Pathology; Pathway interactions; Pharmacologic Substance; Phase; Phenotype; Physiological; Play; Positioning Attribute; Premature aging syndrome; Process; Protein Family; Proteins; Reporting; Research; Role; SIRT1 gene; Signal Transduction; Sirtuins; Starvation; Testing; Tissues; Training; Transport Process; Ubiquitin; Work; Yeasts; age related; aged; anti aging; antimicrobial; chromatin protein; cytokine; design; genome-wide; human disease; in vivo; member; microbial; mortality; mouse model; novel; prevent; proteostasis; response; senescence; tenure track; trafficking; tumor; tumorigenesis

Human aging and a number of age-related diseases are associated with altered protein homeostasis, or proteostasis. Among the critical regulators of proteostasis is autophagy, an evolutionarily conserved membrane trafficking process that degrades a variety of cellular constituents through the lysosome. Autophagy is induced during starvation and calorie restriction, and is essential for maintaining cell and tissue integrity. While autophagy is well-known to degrade cytoplasmic materials, recently I have made the surprising discovery that mammalian autophagy is able to degrade nuclear constituents (Dou et al, Nature, 2015). The autophagy protein LC3 is present in the nucleus and directly interacts with the nuclear lamina protein Lamin B1, and associates with lamin-associated domains (LADs) on chromatin at the genome-wide level. This interaction mediates trafficking and degradation of Lamin B1 and associated heterochromatin, through a nucleus-to- cytoplasm transport process, leading to their digestion in cytoplasmic lysosomes. This lamina and chromatin autodigestion specifically occurs during cellular senescence, a stable form of cell-cycle arrest. Senescence is a specialized cell state in response to oncogene activation, which is beneficial in restraining tumorigenesis; however, senescence is also induced during aging, which contributes to age-related pathologies. I found that inhibiting autophagy or the LC3-Lamin B1 interaction prevents the degradation of Lamin B1 and extends cellular lifespan. These findings provide the first demonstration that mammalian autophagy has functional roles in maintaining homeostasis of the nucleus, suggests a new direction in understanding mammalian aging, and provokes numerous questions to be addressed. In this proposal, I plan to investigate this new perspective of nuclear autophagy, and to study its impact on chromatin and aging. My central hypothesis is that while autophagic degeneration of chromatin is an intrinsic tumor suppressive mechanism, paradoxically it is improperly adapted during aging and contributes to age-related pathologies. I also hypothesize that specific manipulation of this nuclear pathway of autophagy holds promise in treating age-related diseases. For the K99 phase, I propose to study the role of cytoplasmic chromatin shuttled by autophagy in mediating senescence-associated inflammation (Aim 1). I further propose to investigate this pathway in chronic inflammation as seen in human aging, using in vivo aging models (Aim 2). In the R00 phase, I plan to investigate the autophagic degradation of a chromatin modifier that plays an essential role in longevity (Aim 3), and to identify novel nuclear substrates of autophagy that associate with autophagy proteins and regulate senescence and aging (Aim 4). This study will make pioneering contributions to our understanding of mammalian aging from the perspective of nuclear homeostasis, and may help to identify new pharmaceutical targets in ameliorating age-associated disorders. The proposed training and research will greatly facilitate my transition to an independent tenured-track faculty position.

人类衰老和许多与年龄相关的疾病与蛋白质稳态的改变有关， 或蛋白质稳态。自噬是蛋白质稳态的关键调节因子之一，它是一种进化上保守的机制。 通过溶酶体降解多种细胞成分的膜运输过程。自噬 它是在饥饿和热量限制期间诱导的，对于维持细胞和组织的完整性至关重要。 虽然众所周知，自噬会降解细胞质物质，但最近我做了令人惊讶的研究 发现哺乳动物自噬能够降解核成分（Dou 等人，Nature，2015）。这 自噬蛋白 LC3 存在于细胞核中，直接与核纤层蛋白 Lamin B1 相互作用， 并在全基因组水平上与染色质上的核纤层蛋白相关结构域 (LAD) 相关。这次互动 通过核到-介导 Lamin B1 和相关异染色质的运输和降解 细胞质运输过程，导致它们在细胞质溶酶体中消化。该层和染色质 自消化特别发生在细胞衰老过程中，细胞衰老是细胞周期停滞的一种稳定形式。衰老是一种 响应癌基因激活的特化细胞状态，有利于抑制肿瘤发生； 然而，衰老过程中也会诱发衰老，从而导致与年龄相关的病理。我发现 抑制自噬或 LC3-Lamin B1 相互作用可防止 Lamin B1 降解并延长 细胞寿命。这些发现首次证明哺乳动物自噬具有功能性 在维持细胞核稳态中的作用，为理解哺乳动物衰老提供了一个新方向， 并引发了许多需要解决的问题。 在本提案中，我计划研究核自噬的这一新视角，并研究其影响 关于染色质和衰老。我的中心假设是，虽然染色质的自噬变性是一种 内在的肿瘤抑制机制，矛盾的是，它在衰老过程中没有得到适当的适应，并导致 与年龄相关的病理。我还假设对这种自噬核途径的特定操作 有望治疗与年龄相关的疾病。对于K99阶段，我建议研究细胞质的作用 染色质通过自噬穿梭介导衰老相关炎症（目标 1）。我进一步建议 使用体内衰老模型研究人类衰老过程中慢性炎症的这一途径（目标 2）。 在R00阶段，我计划研究染色质修饰剂的自噬降解，该修饰剂起着 在长寿中发挥重要作用（目标 3），并鉴定与自噬相关的新型核底物 自噬蛋白并调节衰老（目标 4）。这项研究将做出开创性贡献 有助于我们从核稳态的角度理解哺乳动物的衰老，并可能有助于 确定改善与年龄相关的疾病的新药物靶标。拟议的培训和 研究将极大地促进我向独立终身教职的过渡。