Redox regulation of thymus function and age-associated dysfunction

 描述(由申请人提供)：T淋巴细胞是免疫的关键介质；然而，由于各种原因，它们在一生中不断丢失，因此必须更换。新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着T细胞的发育和自我耐受、自我限制的T细胞群体的选择。不幸的是，胸腺经历了由年龄引起的急剧萎缩，导致幼稚T细胞产生减少。这种减少引发了外围现有T细胞的扩张，并转向以记忆T细胞为主的寡克隆池，使老年人口对新感染和疫苗的反应较差。因此，预防和/或逆转胸腺萎缩具有延长健康寿命的巨大潜力。由于代表萎缩主要靶点的基质细胞很少，而且很难分离，所以管理年龄诱导的胸腺萎缩的机制一直很难解决。W已经证明，除了在衰老过程中收缩外，基质细胞还会受到功能上的损害，包括诱导自身耐受的机制减少。重要的是，即使再生的器官表面看起来是正常的，这种损伤也不能通过实验再生器官的大小来纠正。因此，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。我们的初步数据有力地表明，间质萎缩受到过氧化氢酶(Cat)缺乏的深刻影响，过氧化氢酶(Cat)负责正常有氧代谢过程中产生的活性氧物种(ROS)的最终解毒，而补充这一缺陷可以缓解胸腺萎缩。我们建议测试终生补充抗氧化剂活性是否可以延长基本胸腺基质功能和幼稚T细胞功能，以及防止萎缩。由于这些研究的潜在结果是治疗性的，我们还建议进行实验，以确定为什么ROS可能对基质细胞有用；ROS的许多生理功能已经被证明，而且基质细胞专门抑制Cat活性的事实表明了对ROS的基本要求。我们将验证这一假设，即ROS诱导的DNA修饰对于诱导基质细胞中组织限制性抗原(TRA)基因的表达，从而诱导中枢耐受是必不可少的。我们还将测试ROS诱导的应激和自噬诱导之间的关系，因为它与自身抗原呈递和耐受性有关。总之，建议的研究旨在全面评估使用抗氧化剂活性来延长免疫功能随年龄增长的有效性和可行性，同时 揭示胸腺生物学和病理学的新机制方面。

 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.