Nucleus-to-cytoplasm trafficking of chromatin fragments in senescence and aging

衰老和衰老过程中染色质片段从核到细胞质的运输

• 批准号: 10722474
• 负责人: Zhixun Dou
• 金额: $ 55.71万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722474
• 关键词: Age; Aging; Biology; Bulla; Capsid; Cell Aging; Cell Cycle Arrest; Cell Nucleus; Cell secretion; Cells; Chromatin; Chronic; Clinical Trials; Complex; Cytoplasm; Cytosol; DNA; DNA Viruses; Development; Disease; Down-Regulation; Electron Transport Complex III; Epigenetic Process; Event; Genetic; Genome; Glucose; Growth Factor; Hepatocyte; Herpesviridae; Immune; Immunologic Surveillance; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Intervention; Knowledge; Link; Liver; Measurement; Mediating; Membrane; Metabolic; Metabolism; Metformin; Microscopy; Modeling; Molecular; Mus; Nuclear; Nuclear Envelope; Nuclear Inner Membrane; Nuclear Lamina; Nuclear Outer Membrane; Nuclear Pore Complex; Oncogenes; Oncogenic; Pathology; Pathway interactions; Peptide Hydrolases; Phenotype; Process; Proteins; Reporting; Research; Role; Severity of illness; Signal Transduction; Stimulator of Interferon Genes; Tissues; Viral; aged; anti aging; antimicrobial; chemokine; cytokine; experimental study; healthy aging; in vitro Model; in vivo; insight; microbial; mouse model; new therapeutic target; novel; nutrient metabolism; pharmacologic; programs; recruit; senescence; tissue regeneration; tool; trafficking; virology

PROJECT SUMMARY Cellular senescence is a stable form of cell cycle arrest program associated with pro-inflammatory responses. Senescent cells accumulate in diseased and aged tissues, where they impair tissue renewal and promote inflammation. Clearance of senescent cells using genetic or pharmacological tools ameliorates disease severity and promotes healthy aging. Therefore, understanding the biology of senescence is an important biomedical objective. The inflammatory program of senescence is a major contributor to the detrimental roles of senescence in aging and disease. Senescent cells secrete a large array of inflammatory cytokines, chemokines, proteases, and growth factors, collectively termed senescence-associated secretory phenotype (SASP). The SASP program recruits immune cells, modulates tissue microenvironment, and ultimately causes inflammation that contributes to most, if not all, age-associated pathologies. Hence, understanding and targeting the SASP program is a major direction in senescence and aging research. Our group contributed to our understanding of the mechanisms of the SASP by showing that the cytosolic DNA sensing cGAS-STING pathway is involved. In senescent cells and aged mouse tissues, chromatin fragments undergo nucleus-to-cytoplasm trafficking, via nuclear membrane blebs that bud off the nuclei, forming cytoplasmic chromatin fragments (CCF). CCF activates cGAS and the SASP program. These results have been independently reproduced by other groups and collectively the CCF-cGAS-STING pathway is considered as one of the central mechanisms that contribute to the SASP program. CCF, by microscopy measurements, is a large entity with an average size of 2 um, which is significantly larger than the capacity of the nuclear pore complex with an upper limit of approximately 100 nm. A key unaddressed question is the mechanism that shuttles the CCF from the nucleus to the cytoplasm. This study investigates a central hypothesis that CCF is shuttled to the cytoplasm via a membrane-trafficking mechanism that resembles viral nuclear egress. First, we propose to investigate the proteins at the inner and outer nuclear membrane that mediate the nuclear egress of CCF and the consequence of the SASP program using senescent cells in vitro. Second, we aim to evaluate the importance of nuclear egress complexes in mediating CCF and the SASP in mouse models of senescence. Third, because aging and inflammation are closely connected with nutrient metabolism, we will further investigate the impact of metabolic alterations on nuclear egress of CCF, focusing on the stability of proteins involved in nuclear egress. This study will provide novel mechanistic insights into the formation of CCF, a key event that triggers the SASP program. This knowledge may facilitate the development of new therapies that target the cytosolic DNA sensing pathway to intervene in aging and age-associated diseases.

项目总结