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: 10682506
• 负责人: Azucena V Rocha
• 金额: $ 1.74万
• 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/10682506
• 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; Communication; Cyclic GMP; Cytoplasm; 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; In Situ; Infection; Inflammation; Inflammation Mediators; Inflammatory; International; Knock-out; Knowledge; Label; Laboratory Research; Longevity; Lung; Maintenance; Malignant Neoplasms; Measures; Mediating; Mentors; Molecular; Molecular Biology; Nuclear; Pathology; Phenotype; Point Mutation; Preparation; Process; Proliferating; Publishing; Recruitment Activity; Repetitive Sequence; Reporting; Research; Risk Factors; Role; Shapes; Signal Transduction; Signaling Molecule; Site; Stress; 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; inhibitor; insight; microbial; novel therapeutic intervention; nuclease; prevent; programs; recombinational repair; recruit; response; senescence; sensor; skills; success; superresolution microscopy; supportive environment; symposium; tool; 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; Communication; Cyclic GMP; Cytoplasm; 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; In Situ; Infection; Inflammation; Inflammation Mediators; Inflammatory; International; Knock-out; Knowledge; Label; Laboratory Research; Longevity; Lung; Maintenance; Malignant Neoplasms; Measures; Mediating; Mentors; Molecular; Molecular Biology; Nuclear; Pathology; Phenotype; Point Mutation; Preparation; Process; Proliferating; Publishing; Recruitment Activity; Repetitive Sequence; Reporting; Research; Risk Factors; Role; Shapes; Signal Transduction; Signaling Molecule; Site; Stress; 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; inhibitor; insight; microbial; novel therapeutic intervention; nuclease; prevent; programs; recombinational repair; recruit; response; senescence; sensor; skills; success; superresolution microscopy; 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.

项目摘要 衰老的特征是总体健康的总体下降和多个逐渐恶化 器官系统。但是，我们对衰老过程的理解以及我们是否可以改善健康范围 仍然是积极研究的话题。衰老的标志之一是细胞衰老，这是一种压力反应， 通过导致不可逆的细胞周期停滞来限制受损细胞的传播。 DNA损伤响应是 导致衰老的关键事件之一。早期衰老的细胞显示卫星转录增加 和丝粒的不稳定性和畸形，称为卫星衰老相关的扩张 （悲伤）。环状GMP-AMP合酶（CGAS）是一种识别和反应的胞质先天免疫传感器 到微生物和自我-DNA。细胞质CGA对于建立衰老和分泌至关重要 炎症介质的衰老特征。但是，对CGAS的沉积和功能知之甚少 在核中。据报道，核CGA通过同源抑制DNA损伤反应（DDR） 细胞核中的重组（HR），并在重复序列（例如centromeres和long）上富集 散布的核元件（线）DNA重复。尽管最近发现了这些发现，但问题仍然是 CGA通过调节HR修复以及CGAS浓度是否在丝粒中促进衰老的进入 线条在早期衰老的SAD形成中起作用。要回答这些问题，我提出了 以下两个目标：AIM 1将确定CGA的DDR抑制是否有助于细胞进入 衰老。 AIM 2将确定CGA在衰老中的SADS形成中是否起作用。结果 该项目将提供有关核CGA在DDR和Centromere稳定性的影响的机械洞察力， 及其在衰老的建立中的作用。促进我们对核CGA的了解可以进一步发展 努力将CGA抑制剂作为潜在的抗炎或抗衰老疗法作为扩展的策略 健康的寿命。 该提案将是第一个使用核CGA与衰老之间关系的提案 成像和独特的专业知识的尖端技术在重复元素上的​​影响力。其中之一 奖学金的培训目标是发展技能和知识体系的曲目，以实现成功的职业 衰老研究的生物学。第二个目标是在有效地传达研究中的经验 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，在国家和国际会议上举行，我的赞助商的指导将确保 这个培训计划的成功。此外，该提议将在 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计划。 该研究和培训计划的完成将推动衰老领域的生物学前进，并为我提供 领导独立学术研究实验室的职业目标的理想准备。