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

• 批准号: 9450159
• 负责人: Ann Venables Griffith
• 金额: $ 5.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 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/9450159
• 关键词: Address; Age; Age-Months; Aging; Antigen Presentation; Antigens; Antioxidants; Atrophic; Autoantigens; Autoimmune Responses; Autophagocytosis; Biological Preservation; 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; 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; immune function; immunosenescence; improved functioning; microorganism antigen; novel; novel strategies; pathogen; prevent; programs; public health relevance; restoration; tool; transcription factor

 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（申请人提供）：T 淋巴细胞是免疫的关键介质；然而，它们在一生中由于各种原因不断丢失，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T细胞发育和自我耐受、自我限制的T细胞群的选择。不幸的是，胸腺会经历年龄引起的急剧萎缩，导致幼稚 T 细胞产生减少。这种减少会引发外周现有 T 细胞的扩张，并转向以记忆 T 细胞为主的寡克隆库，从而导致老年人群对新感染和疫苗的反应较弱。因此，预防和/或逆转胸腺萎缩对于延长健康寿命具有巨大的潜力。控制年龄引起的胸腺萎缩的机制一直难以解决，因为代表萎缩的主要目标的基质细胞很少且难以分离。研究表明，除了衰老过程中的收缩外，基质细胞的功能也会受损，包括诱导自我耐受的机制减少。重要的是，这种损伤并不能通过实验再生器官的大小来纠正，即使再生的器官表面上看起来正常。因此，保存胸腺功能似乎需要防止导致加速萎缩的损伤，而不是简单地恢复大小。我们的初步数据强烈表明，基质萎缩受到过氧化氢酶（Cat）缺乏的严重影响，过氧化氢酶负责正常有氧代谢过程中产生的活性氧（ROS）的最终解毒，而补充这种缺陷可以减轻胸腺萎缩。我们建议测试终身补充抗氧化活性是否可以延长重要的胸腺基质功能和幼稚 T 细胞功能，并防止萎缩。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来确定为什么 ROS 在基质细胞中可能有用； ROS 的许多生理功能已被证明，并且基质细胞特异性抑制 Cat 活性的事实表明 ROS 是必需的。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的组织限制性抗原 (TRA) 基因表达至关重要，从而诱导中枢耐受。我们还将测试 ROS 诱导的应激与自噬诱导之间的关系，因为它与自身抗原的呈递和耐受性有关。总之，拟议的研究旨在全面评估利用抗氧化活性来延长免疫功能随年龄增长的功效和可行性，同时 揭示胸腺生物学和病理学的新机制。