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.

项目摘要 细胞衰老是与促炎反应相关的细胞周期停滞程序的稳定形式。 衰老细胞在患病和衰老的组织中积累，在那里它们损害组织更新并促进组织再生。 炎症使用遗传或药理学工具清除衰老细胞可改善疾病严重程度 促进健康衰老。因此，了解衰老的生物学是一个重要的生物医学 objective. 衰老的炎症程序是衰老的有害作用的主要贡献者 和疾病衰老细胞分泌大量的炎性细胞因子、趋化因子、蛋白酶， 生长因子，统称为衰老相关分泌表型（SASP）。SASP计划 招募免疫细胞，调节组织微环境，最终导致炎症， 大多数甚至全部与年龄相关的疾病因此，了解和瞄准SASP计划是一个主要的 衰老和衰老研究方向。 我们的研究小组通过显示细胞质DNA的变化， 检测cGAS-STING途径。在衰老细胞和老年小鼠组织中， 通过从细胞核出芽的核膜泡进行细胞核到细胞质的运输， 细胞质染色质片段（CCF）。CCF激活cGAS和SASP程序。这些结果已经 CCF-cGAS-STING途径被认为是由其他组独立地复制的，并且共同地被认为是一个 为SASP计划做出贡献的中央机制。 通过显微镜测量，CCF是一个平均尺寸为2 μ m的大实体， 比核孔复合物的容量高，上限约为100 nm。一个没有地址的钥匙 问题是CCF从细胞核穿梭到细胞质的机制。本研究调查了 核心假设是CCF通过膜运输机制穿梭于细胞质， 类似于病毒核出口首先，我们打算研究内核和外核的蛋白质 膜介导CCF的核出口和SASP程序使用衰老的结果 体外细胞第二，我们的目的是评估核出口复合物在介导CCF中的重要性， 小鼠衰老模型中的SASP。第三，因为衰老和炎症与 营养代谢，我们将进一步研究代谢改变对CCF核出口的影响， 集中于涉及核出口的蛋白质的稳定性。 本研究将为CCF的形成提供新的机制见解，CCF是触发SASP的关键事件 程序.这一知识可能有助于开发靶向细胞溶质DNA传感的新疗法。 干预衰老和年龄相关疾病的途径。