The role of cGAS in Senesence and the formation of SADS

项目摘要 老龄化的特征是总体健康状况普遍下降，并在多个阶段逐渐恶化 器官系统。然而，我们对衰老过程的理解以及我们是否可以提高健康寿命 仍然是一个积极研究的主题。衰老的标志之一是细胞衰老，这是一种压力反应， 通过引起不可逆的细胞周期停滞来限制受损细胞的繁殖。DNA损伤的反应是 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 着丝粒不稳定和畸形，称为与衰老相关的卫星扩张 (SADS)。环状GMP-AMP合成酶(CGAS)是一种胞质天然免疫感受器，识别和响应 微生物和自身DNA。细胞质中的cGAs对衰老的建立和分泌是必不可少的 以衰老为特征的炎性介质。然而，对cGAS的沉积和功能知之甚少 在原子核中。据报道，核cGAs通过同源基因抑制DNA损伤反应(DDR)。 核内的重组(HR)，并在着丝粒和长着丝粒等重复序列上富含 穿插的核元素(线)DNA重复。尽管最近有这些发现，但问题仍然是 CGAS通过调节HR修复和着丝粒cGAS浓度是否参与衰老进入 在早衰过程中，品系在SADS的形成中起着重要作用。为了回答这些问题，我建议 以下两个目标：目标1将确定cGAS抑制DDR是否有助于细胞进入 衰老。目的2将确定cGAS是否在衰老过程中SADS的形成中起作用。调查结果： 这个项目将提供关于核cGAs在DDR和着丝粒稳定性中的作用的机械性见解， 以及它在衰老形成过程中的作用。推进我们对核cGAS的了解可以进一步 努力开发cGAS抑制剂作为潜在的抗炎或抗衰老疗法，作为延伸的策略 健康的寿命。 这项提议将是第一次研究核cGAs和衰老之间的关系 在成像方面的尖端技术和独特的专业知识在重复元素上的影响。这其中的一个 联谊会的培训目标是发展技能和知识体系，以便在以下领域取得成功 衰老研究的生物学。第二个目标是获得在有效沟通研究方面的经验 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，以及我的赞助者的指导将确保 这项培训计划的成功。此外，这项建议将在 布朗大学跨学科和支持性的分子生物学、细胞生物学和生物化学课程。 这项研究和培训计划的完成将推动衰老生物学领域的发展，并为我提供 领导一个独立的学术研究实验室的职业目标的理想准备。

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.