Redox regulation of thymus function and age-associated dysfunction

胸腺功能和年龄相关功能障碍的氧化还原调节

基本信息

批准号：
9902004
负责人：
Ann Venables Griffith
金额：
$ 4.01万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902004
关键词：
Address Age Age-Months Aging Antigen Presentation Antigens Antioxidants Atrophic Autoantigens Autoimmune Responses Autophagocytosis Biology Castration Cell Respiration Cell physiology Cells Collaborations Complement Contracts DNA DNA Modification Process Data Dose Drug Metabolic Detoxication Elderly Emigrant Environment Enzymes Epithelial Functional disorder Gene Expression Gene Expression Profile Generations Genetic Immune response Immunity Immunology Impairment In Situ Infection Knockout Mice Life Lymphoid Maintenance Measures Mediating Mediator of activation protein Modification Mus Natural regeneration Nude Mice Organ Organ Size Outcome Outcome Study Oxidation-Reduction Pathogenesis Pathogenicity Pathology Pathway interactions Peptides Physiological Population Prevention Production Proteins Reactive Oxygen Species Regimen Regulation Reporter Role Self Tolerance Site Stress Stromal Cells Supplementation T memory cell T-Cell Development T-Lymphocyte Testing Therapeutic Thymic epithelial cell Thymus Gland Tissues Transgenic Mice Translating Transplantation Vaccines Water Weaning aged autoreactive T cell catalase central tolerance complement deficiency crosslink dietary antioxidant experimental study functional decline functional disability healthspan immune function immunosenescence improved functioning microorganism antigen novel novel strategies pathogen preservation prevent programs public health relevance restoration tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): T lymphocytes are critical mediators of immunity; however they are continuously lost for a variety of reasons throughout life, and therefore must be replaced. Generation of new T cells is the function of the thymus, and the unique stromal microenvironment in the thymus directs T cell development and the selection of self- tolerant, self-restricted T cell population. Unfortunately, the thymus undergoes a precipitous age-induced atrophy resulting in reduced naïve T cell production. This reduction triggers an expansion of existing T cells in the periphery, and a shift towards an oligoclonal pool dominated by memory T cells, leaving the elderly population less responsive to new infections and vaccines. Preventing and/or reversing thymic atrophy therefore hold significant potential for healthspan extension. The mechanisms governing age-induced thymic atrophy has been difficult to resolve because stromal cells, which represent the primary targets of atrophy, are rare and difficult to isolate. W have shown that in addition to contracting during aging, stromal cells are also functionally impaired, including a reduction in mechanisms that induce tolerance to self. Importantly, this impairment is not corrected by regenerating the size of the organ experimentally, even though the regenerated organ appears superficially normal. Thus, preservation of thymic function appears to require preventing the damage that leads to accelerated atrophy, rather than simple restoration of size. Our preliminary data strongly suggest that stromal atrophy is profoundly impacted by deficiency in the enzyme catalase (Cat), which is responsible for terminal detoxification of reactive oxygen species (ROS) produced during normal aerobic metabolism, and that complementation of this deficiency mitigates thymic atrophy. We propose to test whether lifelong complementation of antioxidant activity can prolong essential thymic stromal functions and naïve T cell function, as well as preventing atrophy. Since a potential outcome of these studies is therapeutic, we also propose performing experiments to determine why ROS may be useful in stromal cells; numerous physiological functions for ROS have been demonstrated, and the fact that stromal cells specifically repress Cat activity suggests an essential requirement for ROS. We will test the hypothesis that ROS-induced modifications to DNA are essential for induction of tissue restricted antigen (TRA) gene expression in stromal cells, and thus for the induction of central tolerance. We will also test the relationship between ROS-induced stress and the induction of autophagy, as it relates to self-antigen presentation and tolerance. Together, the proposed studies aim to comprehensively assess the efficacy and feasibility of using antioxidant activity to prolong immune function with age, while simultaneously uncovering novel mechanistic aspects of thymic biology and pathology.

描述（由适用提供）：T淋巴细胞是免疫力的关键介体；但是，由于一生中的各种原因，它们不断丢失，因此必须更换。新的T细胞的产生是胸腺的功能，胸腺中独特的基质微环境指导T细胞发育和选择自耐自由的T细胞种群。不幸的是，胸腺经历了精确的年龄引起的萎缩，导致幼稚的T细胞产生降低。这种减少触发了外围现有T细胞的扩展，并朝着由记忆T细胞支配的寡聚池的转移，使老年人群对新的感染和疫苗的反应较低。因此，预防和/或逆转胸腺萎缩具有巨大的健康范围扩展潜力。管理年龄诱导的胸腺萎缩的机制很难解决，因为代表萎缩的主要靶标的基质细胞很少见。 W显示，除了在衰老期间收缩外，基质细胞在功能上也受到损害，包括降低诱导自我耐受性的机制。重要的是，即使再生器官看起来超正常，也无法通过在实验上再生器官的大小再生来纠正这种障碍。这就是胸腺功能的保存似乎需要防止导致加速萎缩的损害，而不是简单地恢复大小。我们的初步数据强烈表明，基质萎缩受到酶过氧化氢酶（CAT）缺乏的深远影响，该酶过氧化酶（CAT）负责在正常有氧代谢过程中产生的活性氧（ROS）的终末排毒，并且该缺乏症的乳化性乳化性胸膜疾病的缺乏。我们建议测试终身完成抗氧化活性是否可以延长基本的胸腺基质功能和幼稚的T细胞功能，并预防萎缩。由于这些研究的潜在结果是治疗性的，因此我们还提出了执行实验，以确定为什么ROS在基质细胞中可能有用。已经证明了许多ROS的物理功能，并且基质细胞专门反映CAT活性这一事实表明ROS的必要性。我们将检验以下假设：ROS诱导的DNA修饰对于诱导基质细胞中组织限制的抗原（TRA）基因表达至关重要，因此对于引入中心耐受性至关重要。我们还将测试ROS诱导的压力与自噬的引入之间的关系，因为它与自我抗原的表现和耐受性有关。共同拟议的研究旨在全面评估使用抗氧化活性随着年龄延长免疫功能的效率和可行性，而同样地揭示胸腺生物学和病理学的新机械方面。