Telomere Damage Responses and Immune Aging

端粒损伤反应和免疫衰老

基本信息

批准号：
8787448
负责人：
Cornelia M. Weyand
金额：
$ 43.44万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-20 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8787448
关键词：
ATR gene Affect Age Aging Aging-Related Process Apical Apoptosis Apoptotic Autoimmune Process BRCA1 gene Behavior Binding Binding Proteins Biological Models CD4 Positive T Lymphocytes Cardiovascular Diseases Cell Aging Cell Cycle Checkpoint Cell Proliferation Cell Survival Cell physiology Cells Chromatin Chromosomes Chronic Clonal Expansion Cohort Studies Competence DNA DNA Damage DNA Repair DNA Repair Pathway DNA strand break Defect Deterioration Disease Disease remission Effectiveness Elderly Employee Strikes Event Failure Functional disorder Generations Health Hematopoietic Homeostasis Human Immune Immune response Immune system Immunity Immunodeficient Mouse Individual Infection Inflammation Inflammatory Influenza vaccination Knowledge Life Expectancy Life Style Longevity Maintenance Malignant Neoplasms Measures Memory Molecular Molecular Profiling Morbidity - disease rate Pathology Patients Phenotype Phosphotransferases Preclinical Testing Predisposition Process Puma Regulation Regulatory T-Lymphocyte Rest Rheumatoid Arthritis Role Signal Transduction Stress Syndrome T memory cell T-Lymphocyte T-Lymphocyte Subsets Telomere Shortening Testing Therapeutic Intervention Tissues Topoisomerase age related aged burden of illness cell age cohort combat cytokine design frailty healthy aging high risk immune function improved in vivo indexing influenza virus vaccine mouse model muscle strength novel novel therapeutics offspring overexpression premature progenitor prospective reconstitution repaired research study response restoration senescence sensor telomere telomere loss

项目摘要

DESCRIPTION (provided by applicant): 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 indispensable 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.

描述（由申请人提供）：人类免疫系统的逐渐衰竭极大地阻碍了寿命和晚年生活质量的进步，而保护宿主免受感染和恶性肿瘤的保护性免疫力的丧失与慢性闷烧的增加有关。衰老引起的免疫恶化的分子机制尚不清楚，患有自身免疫综合征、类风湿性关节炎 (RA) 的患者的免疫衰老过程会加速约 25 年。患者罹患与年龄相关的疾病的风险较高，例如 RA 患者的 T 细胞中的端粒因年龄而缩短；但更重要的是，一些染色体具有无端粒末端并发生端粒融合。损伤与 ATR-Chk1 DNA 修复途径无效有关。在 RA T 细胞和 75 岁以上个体的 T 细胞中，端粒负载增加。 ATR 的结合，但 ATR 不可或缺的激活剂 TopBP1 的结合却减弱了。该提案旨在从机制水平上了解受损端粒产生的 DNA 损伤反应、它们如何促进免疫衰老过程以及端粒损伤如何产生偏差。 T 细胞远离炎症的保护性免疫在特定目标 1 中，我们将定义年轻和年老 T 细胞中受应激端粒的 DNA 损伤反应的分子成分。具体目标 2 检查宿主的渐进年龄和炎症状态如何影响端粒损伤修复以及由此产生的细胞反应。这些实验将建立在两个研究队列的基础上：健康老龄化、生活方式和虚弱 (HALF) 队列，由健康的老年人组成。 30-90 岁和斯坦福类风湿关节炎 (STAR) 队列（类风湿关节炎患者的前瞻性队列）我们将量化端粒 TopBP1-ATR 模块与年龄增长的关系。 RA 疾病负担。具体目标 3 将揭示端粒损伤对 T 细胞命运、克隆扩增和功能承诺的影响。通过设置有意的端粒损伤，我们将研究端粒依赖性损伤机制对 T 细胞凋亡和承诺的影响。此外，我们将探讨端粒损伤是否与老年人流感疫苗的有效性相关。在具体目标 4 中，我们将探讨 Th1、Th2、Th17、Tfh 和 Treg 谱系的作用。这些实验依靠用人类 T 细胞重建免疫缺陷小鼠来测量其稳态扩张、细胞凋亡敏感性和 na 。 ¿总体而言，该提案有望提供对衰老端粒发生的分子事件的新认识，并利用这些知识开发新的治疗策略来对抗免疫衰老。