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有关的细胞周期停滞计划的稳定形式。 衰老细胞积聚在患病和老化的组织中，它们会损害组织的更新并促进 炎。使用遗传或药理学工具清除衰老细胞可改善疾病的严重程度 并促进健康的衰老。因此，了解衰老的生物学是重要的生物医学 客观的。 衰老的炎症计划是导致衰老中衰老有害作用的主要因素 和疾病。衰老细胞分泌大量炎性细胞因子，趋化因子，蛋白酶和 生长因子共同称为衰老相关的分泌表型（SASP）。 SASP程序 募集免疫细胞，调节组织微环境，并最终引起炎症 对于大多数（如果不是全部），与年龄相关的病理学。因此，理解和针对SASP程序是主要的 衰老和衰老研究的方向。 我们的小组通过表明胞质DNA来帮助我们理解SASP的机制 涉及感知CGAS刺道途径。在衰老细胞和老年小鼠组织中，染色质片段 通过核膜爆发，从细胞核中造成细胞核的细胞质运输，形成 细胞质染色质片段（CCF）。 CCF激活CGA和SASP程序。这些结果是 由其他群体独立复制并共同复制了CCF-CGAS丁字道是一个 有助于SASP程序的中心机制。 通过显微镜测量，CCF是一个平均大小为2 um的大实体，它明显更大 比核孔复合物的容量大约100 nm。钥匙未解决 问题是将CCF从核从细胞核中延伸到细胞质的机制。这项研究调查了 中央假设CCF通过膜贩运机制将CCF穿梭到细胞质上 类似于病毒核出口。首先，我们建议研究内部和外部核的蛋白质 介导CCF核出口的膜和SASP程序的后果 细胞体外。其次，我们旨在评估核出口复合物在中介CCF和 SASP在衰老的小鼠模型中。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， 专注于参与核出口的蛋白质的稳定性。 这项研究将为CCF的形成提供新的机械见解，这是一个触发SASP的关键事件 程序。这些知识可能促进针对胞质DNA感应的新疗法的发展 干预衰老和年龄相关疾病的途径。