The role of cGAS in Senesence and the formation of SADS

cGAS 在衰老和 SADS 形成中的作用

• 批准号: 10231400
• 负责人: Azucena V Rocha
• 金额: $ 4.6万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231400
• 关键词: Address; Age; Aging; Anti-Inflammatory Agents; Attenuated; Biochemistry; Biology of Aging; Cell Aging; Cell Cycle Arrest; Cell Nucleus; Cells; Cellular Stress; Cellular biology; Centromere; ChIP-seq; Characteristics; Chromatin; Chronic; Cyclic GMP; Cytosol; DNA; DNA Damage; DNA Repair; Data; Dementia; Deposition; Deterioration; Diabetes Mellitus; Diploidy; Elements; Ensure; Event; Extracellular Matrix Proteins; Fellowship; Fibroblasts; Genetic Transcription; Genome; Genomics; Goals; Growth Factor; Health; Human; Image; Immune; Infection; Inflammation; Inflammation Mediators; Inflammatory; International; Knock-out; Knowledge; Label; Laboratory Research; Lead; Longevity; Lung; Maintenance; Malignant Neoplasms; Measures; Mediating; Mentors; Microscopy; Molecular; Molecular Biology; Nuclear; Pathology; Phenotype; Play; Point Mutation; Preparation; Process; Proliferating; Publishing; Recruitment Activity; Repetitive Sequence; Reporting; Research; Research Training; Resolution; Risk Factors; Role; Shapes; Signal Transduction; Signaling Molecule; Site; Stress; Structure; Technology; Testing; Time; Training; Universities; Work; age related; anti aging; biological adaptation to stress; body system; career; cell injury; chemokine; chronic inflammatory disease; collaborative environment; cytokine; environmental stressor; experience; healthspan; homologous recombination; improved; in situ sequencing; inhibitor/antagonist; insight; microbial; novel therapeutic intervention; nuclease; prevent; programs; recombinational repair; recruit; response; senescence; sensor; skills; success; supportive environment; symposium; tool

Project Summary Aging is characterized by a general decline in overall health and a gradual deterioration across multiple organ systems. However, our understanding of the aging process and whether we can improve health span remains a topic of active research. One of the hallmarks of aging is cellular senescence, a stress response that limits the propagation of damaged cells by causing irreversible cell cycle arrest. The DNA damage response is one of the key events leading to senescence. Cells in early senescence show increased satellite transcription and centromere instability and dysmorphism, known as the senescence-associated distension of satellites (SADS). Cyclic GMP-AMP synthase (cGAS) is a cytosolic innate immune sensor that recognizes and responds to microbial and self-DNA. Cytoplasmic cGAS is essential for the establishment of senescence and the secretion of inflammatory mediators characteristic of senescence. However, little is known of cGAS deposition and function in the nucleus. Nuclear cGAS has been reported to inhibit the DNA Damage Response (DDR) via homologous recombination (HR) in the nucleus and to be enriched at repetitive sequences such as centromeres and long interspersed nuclear element (LINE) DNA repeats. Despite these recent findings, the question remains whether cGAS contributes to senescence entry by modulating HR repair and whether cGAS concentration at centromeres and LINEs plays a role in the formation of SADS in early senescence. To answer these questions, I propose the following two aims: Aim 1 will determine whether cGAS inhibition of the DDR contributes to cell entry into senescence. Aim 2 will determine whether cGAS plays a role in SADS formation in senescence. The findings of this project will provide mechanistic insight on the effect of nuclear cGAS in the DDR and centromere stability, and its role in the establishment of senescence. Advancing our knowledge of nuclear cGAS can further current efforts to develop inhibitors of cGAS as potential anti-inflammatory or anti-aging therapy as strategies that extend healthy lifespan. This proposal will be the first to examine the relationship between nuclear cGAS and senescence using cutting edge technology in imaging and unique expertise in its influence at repetitive elements. One of this fellowship's training goals is to develop the repertoire of skills and body of knowledge for a successful career in the biology of aging research. The second goal is to gain experience in effectively communicating research in a variety of settings. To achieve these goals, completion of the proposed research, attending the Gordon Research Conference, presenting at national and international conferences, and my sponsor's mentoring will ensure the success of this training plan. Furthermore, this proposal will take place in the excellent environment of the interdisciplinary and supportive Molecular Biology, Cell Biology, and Biochemistry program at Brown University. Completion of this research and training plan will move the biology of aging field forward and provide me with the ideal preparation towards the career goal of leading an independent academic research laboratory.

项目概要 老龄化的特点是整体健康状况普遍下降，多个方面逐渐恶化。 器官系统。然而，我们对衰老过程的了解以及我们是否可以改善健康寿命 仍然是一个活跃的研究课题。衰老的标志之一是细胞衰老，这是一种应激反应， 通过引起不可逆的细胞周期停滞来限制受损细胞的增殖。 DNA损伤反应是 导致衰老的关键事件之一。早期衰老细胞显示卫星转录增加 着丝粒不稳定和畸形，称为衰老相关卫星扩张 （SADS）。环 GMP-AMP 合酶 (cGAS) 是一种胞质先天免疫传感器，可识别并做出反应 微生物和自身 DNA。细胞质 cGAS 对于衰老的建立和分泌至关重要 衰老特征的炎症介质。然而，人们对 cGAS 的沉积和功能知之甚少 在细胞核中。据报道，核 cGAS 可通过同源酶抑制 DNA 损伤反应 (DDR) 重组（HR）在细胞核中，并在重复序列（例如着丝粒和长序列）处富集 散布的核元件 (LINE) DNA 重复序列。尽管有这些最近的发现，问题仍然是： cGAS 通过调节 HR 修复以及着丝粒处的 cGAS 浓度来促进衰老进入 LINEs在衰老早期SADS的形成中发挥作用。为了回答这些问题，我建议 以下两个目标：目标 1 将确定 DDR 的 cGAS 抑制是否有助于细胞进入 衰老。目标 2 将确定 cGAS 是否在衰老过程中 SADS 的形成中发挥作用。调查结果 该项目将为核 cGAS 对 DDR 和着丝粒稳定性的影响提供机制见解， 及其在衰老过程中的作用。提高我们对核 cGAS 的了解可以进一步推动当前 努力开发 cGAS 抑制剂作为潜在的抗炎或抗衰老疗法，作为延长治疗时间的策略 健康的寿命。 该提案将是第一个利用核 cGAS 和衰老之间的关系进行研究的提案 尖端的成像技术和独特的专业知识对重复元素的影响。其中之一 奖学金的培训目标是发展技能和知识体系，以实现成功的职业生涯 衰老研究的生物学。第二个目标是获得有效交流研究的经验 各种设置。为了实现这些目标，完成拟议的研究，参加戈登研究 会议、在国内和国际会议上发表演讲以及我的赞助商的指导将确保 本次培训计划的成功。此外，本提案将在良好的环境下进行 布朗大学的跨学科和支持性分子生物学、细胞生物学和生物化学项目。 这项研究和培训计划的完成将推动衰老领域的生物学向前发展，并为我提供 为领导独立学术研究实验室的职业目标做好理想的准备。