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有关的疾病都与蛋白质体内平衡的改变有关，