Telomere Damage Responses and Immune Aging

项目摘要 人类的逐渐失败极大地阻碍了寿命和晚年生活质量的提高 保护宿主免受感染和恶性肿瘤的免疫系统。失去保护性免疫力是 与慢性阴燃发炎综合症的增加有关。潜在的分子机制 人们对衰老引起的免疫恶化的认识还不够深入。免疫老化进程加快 在患有自身免疫综合征的患者中，类风湿性关节炎(RA)大约25年，这些患者是 患与年龄相关疾病的风险更高，如心血管疾病。类风湿关节炎患者T细胞中的端粒 患者的年龄不适当地缩短了；但更重要的是，一些染色体没有端粒。 结束并进行端粒融合。这种端粒损伤的表型与端粒的无效有关。 ATR-Chk1 DNA修复途径。在RA T细胞和75岁以上的T细胞中，端粒携带有 ATR的负荷增加，但ATR不可或缺的激活剂TopBP1的结合减少。这项建议 旨在从机械论的层面上理解DNA损伤反应 损伤的端粒，它们如何在免疫老化过程中起作用，以及端粒如何损伤 使T细胞从保护性免疫转向炎症。在具体目标1中，我们将定义 年轻和老年T细胞端粒DNA损伤反应的分子成分。我们会 在具体目标2中进行，以检查进展性年龄和宿主的炎症状态如何影响 端粒损伤修复和由此产生的细胞反应。这些实验将建立在两项研究的基础上 队列；由30-90岁的健康个体组成的健康老龄化、生活方式和虚弱(一半)队列 年和斯坦福大学类风湿性关节炎(STAR)队列，类风湿患者的预期队列 关节炎。我们将量化端粒TopBP1-ATR模块与增龄和RA疾病的关系 负担。具体目标3将揭示端粒损伤对T细胞命运、克隆性增殖和 功能承诺。通过设置故意的端粒损伤，我们将研究端粒的影响- 依赖损伤机制对T细胞凋亡及对Th1、Th2、Th17、Tfh和Treg的影响 血统。此外，我们还将探讨端粒损伤是否与流感疫苗的有效性有关。 老年人。在特定的目标4中，我们将探索端粒去封顶在免疫衰老过程中的作用。 并建立一个旨在减缓T细胞衰老的治疗干预的临床前测试平台。这些 实验依赖于免疫缺陷小鼠与人类T细胞的重建来测量它们的 动态平衡扩张，它们的凋亡敏感性和它们的NA到记忆的转换。总体而言，这 该提案承诺提供对发生在老化端粒上的分子事件的新理解，并 利用这一知识开发新的治疗策略来对抗免疫老化。

Project Summary Advancements in longevity and later-life quality are hampered greatly by the progressive failure of the human immune system which protects the host from infections and malignancies. Loss of protective immunity is associated with the gain of a chronic, smoldering inflammatory syndrome. Molecular mechanisms underlying aging-induced immune deterioration are insufficiently understood. The process of immune aging is accelerated in patients with the autoimmune syndrome rheumatoid arthritis (RA) by about 25 years and these patients are at higher risk for age-related morbidities, such as cardiovascular disease. Telomeres in T cells from RA patients are age-inappropriately shortened; but, more importantly, some chromosomes have telomere-free ends and undergo telomeric fusions. This phenotype of telomeric damage is related to ineffectiveness of the ATR-Chk1 DNA repair pathway. In RA T cells and in T cells from individuals >75 years, telomeres carry an increased load of ATR, yet binding of TopBP1, an indispensible activator of ATR, is diminished. This proposal is designed to understand on a mechanistic level the DNA damage responses emanating from damaged telomeres, how they contribute to the process of immune aging and how telomeric damage biases T cells away from protective immunity towards inflammation. In Specific Aim 1, we will define the molecular components of the DNA damage response at stressed telomeres in young and old T cells. We will proceed in Specific Aim 2 to examine how progressive age and the inflammatory status of the host affect telomeric damage repair and the resulting cellular response. These experiments will build on two study cohorts; the Healthy Aging, Lifestyle and Frailty (HALF) cohort composed of healthy individuals aged 30-90 years and the Stanford Rheumatoid Arthritis (STAR) cohort, a prospective cohort of patients with rheumatoid arthritis. We will quantify the telomeric TopBP1-ATR module in relation to advancing age and RA disease burden. Specific Aim 3 will reveal the consequences of telomeric damage on T cell fate, clonal expansion and functional commitment. By setting intentional telomere damage we will study the impact of the telomere- dependent damage machinery on T cell apoptosis and commitment to the Th1, Th2, Th17, Tfh and Treg lineage. Also, we will explore whether telomere damage correlates with effectiveness of an influenza vaccine in the elderly. In Specific Aim 4, we will explore the role of telomeric uncapping on the immune aging process in vivo and build a preclinical testing platform for therapeutic interventions aimed at slowing T cell aging. These experiments rely on the reconstitution of immunodeficient mice with human T cells to measure their homeostatic expansion, their apoptotic susceptibility and their na¿ve-to-memory conversion. Overall, this proposal promises to provide new understanding of the molecular events that occur at aging telomeres and to utilize that knowledge to develop novel therapeutic strategies to combat immune aging.