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: 9314111
• 负责人: Zhixun Dou
• 金额: $ 11.07万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9314111
• 关键词: ADP Ribose Transferases; Address; Age; Aging; Area; Autophagocytosis; Caloric Restriction; Cell Aging; Cell Cycle Arrest; Cell Nucleus; Cells; Chromatin; 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有关的疾病与蛋白质稳态改变有关， 或蛋白毒酸。在蛋白抑制的关键调节剂中，是自噬，一种进化保守的 膜运输过程通过溶酶体降解了各种细胞成分。自噬 在饥饿和卡路里限制期间诱导，对于维持细胞和组织完整性至关重要。 虽然自噬众所周知会降解细胞质材料，但最近我做了令人惊讶的 发现哺乳动物自噬能够降解核成分（Dou等人，自然，2015年）。这 自噬蛋白LC3存在于细胞核中，并直接与核薄片蛋白lamin b1相互作用， 并在全基因组水平的染色质上与层蛋白相关结构域（LAD）相关。这种相互作用 通过细胞核介导lamin b1和相关异染色质的运输和降解 细胞质转运过程，导致它们在细胞质溶酶体中的消化。该薄片和染色质 自动消化是在细胞衰老期间特异性发生的，细胞衰老是一种稳定的细胞周期停滞形式。衰老是 专门的细胞态响应癌基因激活，这有益于限制肿瘤发生。 但是，在衰老过程中也诱发衰老，这导致了与年龄有关的病理。我发现 抑制自噬或LC3环蛋白B1相互作用可防止层粘连蛋白B1的降解并延伸 细胞寿命。这些发现提供了第一个演示，即哺乳动物自噬具有功能 在维持细胞核稳态中的作用，这表明了理解哺乳动物衰老的新方向， 并引起许多问题要解决。 在此提案中，我计划调查这种核自噬的新观点，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 固有的肿瘤抑制机制，矛盾的是，它在衰老过程中适应不当，并有助于 与年龄有关的病理。我还假设对这种自噬的核途径的特定操纵 对治疗与年龄有关的疾病有希望。对于K99阶段，我建议研究细胞质的作用 染色质在介导与衰老相关的炎症中被自噬穿梭（AIM 1）。我进一步提出 为了使用体内衰老模型在人衰老中发现的慢性炎症中的这一途径（AIM 2）。 在R00阶段，我计划研究播放的染色质修饰符的自噬降解 在寿命中的重要作用（AIM 3），并确定与与 自噬蛋白质并调节衰老和衰老（AIM 4）。这项研究将做出开创性的贡献 从核稳态的角度来理解哺乳动物衰老的理解，可能有助于 在改善年龄相关疾病中确定新的药物靶标。拟议的培训和 研究将极大地促进我过渡到独立的终身轨道教师职位。