Telomere Damage Responses and Immune Aging

端粒损伤反应和免疫衰老

• 批准号: 8971947
• 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
• 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/8971947
• 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; TP53 gene; Telomere Shortening; Testing; Therapeutic Intervention; Tissues; Topoisomerase; age related; aged; burden of illness; cell age; cohort; combat; cytokine; design; frailty; healthy aging; high risk; humanized mouse; 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

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（由适用提供）：人类免疫系统的进行性失败极大地阻碍了寿命和后期质量的进步，该系统可以保护宿主免受感染和恶性肿瘤的影响。保护性免疫组织化学的丧失与慢性闷烧炎症综合征的增益有关。衰老诱导的免疫端内化的分子机制不足以理解。自身免疫性综合征类风湿关节炎（RA）患者的免疫衰老过程大约25岁，这些患者患年龄相关的病态（例如心血管疾病）的风险较高。来自RA患者的T细胞中的端粒已适当缩短。但是，更重要的是，某些染色体具有无端粒末端并进行远程融合。这种远程损伤的表型与ATR-CHK1 DNA修复途径的无效性有关。在> 75年的个体中，在RA T细胞和T细胞中，端粒载有ATR的载荷增加，但TopBP1的结合是ATR的必不可少的激活剂，但端粒的结合减少了。该建议旨在从机械水平上理解DNA损伤反应受损的端粒产生，它们如何促进免疫衰老的过程以及远程仪损伤如何使T细胞从保护性免疫中偏向炎症。在特定的目标1中，我们将定义年轻和老T细胞中应力端粒的DNA损伤反应的分子成分。我们将继续以特定的目标2来研究宿主的渐进式年龄和炎症状态如何影响远程遗传损伤修复和所得的细胞反应。这些实验将基于两个研究队列。由30-90岁的健康个体组成的健康衰老，生活方式和脆弱（一半）队列，以及斯坦福类风湿关节炎（Star）群体，这是一群类风湿关节炎患者的前瞻性队列。我们将量化远程远程BP1-ATR模块，以相对于促进年龄和RA疾病Burnen。特定的目标3将揭示远程损伤对T细胞命运，克隆扩张和功能承诺的后果。通过设定有意的端粒损伤，我们将研究端粒依赖性损伤机制对T细胞凋亡以及对TH1，TH2，TH17，TFH和Treg谱系的承诺的影响。另外，我们将探索端粒损伤是否与造成影响疫苗的有效性相关。在特定的目标4中，我们将探索远程固定在体内免疫过程中的作用，并为旨在减慢T细胞老化的治疗干预措施建立临床前测试平台。这些实验依赖于与人T细胞的免疫缺陷小鼠的重构来测量其稳态膨胀，凋亡敏感性以及其NATO-VE-MEMORY转换。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理解，并利用这些知识来开发新颖的治疗策略来打击免疫衰老。