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（由申请人提供）：人类免疫系统（保护宿主免受感染和恶性肿瘤）的进行性失效极大地阻碍了寿命和后期生活质量的提高。保护性免疫的丧失与慢性郁积性炎症综合征的获得有关。衰老诱导的免疫功能下降的分子机制还不清楚。自身免疫综合征类风湿性关节炎（RA）患者的免疫老化过程加速约25年，这些患者患年龄相关疾病（如心血管疾病）的风险更高。RA患者T细胞中的端粒与年龄不相称地缩短;但更重要的是，一些染色体具有无端粒末端并进行端粒融合。端粒损伤的这种表型与ATR-Chk 1 DNA修复途径的无效性有关。在RA T细胞和来自>75岁的个体的T细胞中，端粒携带增加的ATR负荷，但ATR的不可或缺的激活剂TopBP 1的结合减少。该提案旨在从机制层面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，以及端粒损伤如何使T细胞远离保护性免疫而偏向炎症。在具体目标1中，我们将定义年轻和老年T细胞中应激端粒DNA损伤反应的分子组成。我们将继续在具体目标2，研究如何渐进的年龄和炎症状态的主机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个研究队列基础上;健康老龄化、生活方式和虚弱（HALF）队列，由30-90岁的健康个体组成;以及斯坦福大学风湿性关节炎（星星）队列，一个类风湿性关节炎患者的前瞻性队列。我们将量化端粒TopBP 1-ATR模块与年龄增长和RA疾病负担的关系。特异性目标3将揭示端粒损伤对T细胞命运、克隆扩增和功能承诺的后果。通过设置故意的端粒损伤，我们将研究端粒依赖性损伤机制对T细胞凋亡和向Th 1、Th 2、Th 17、Tfh和Treg谱系的定型的影响。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，我们将探索端粒脱帽在体内免疫衰老过程中的作用，并为旨在减缓T细胞衰老的治疗干预建立临床前测试平台。这些实验依赖于用人类T细胞重建免疫缺陷小鼠，以测量它们的稳态扩张，它们的凋亡易感性和它们的幼稚记忆转换。总的来说，这项提案有望提供对衰老端粒发生的分子事件的新理解，并利用这些知识开发新的治疗策略来对抗免疫衰老。