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

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,它们在一生中会因各种原因而不断丢失,因此必须由胸腺和独特的基质产生新的 T 细胞。胸腺中的微环境指导 T 细胞的发育和自我耐受、自我限制的 T 细胞群的选择,不幸的是,胸腺经历了年龄引起的急剧萎缩,导致幼稚 T 细胞减少。这种减少会引发外周现有 T 细胞的扩增,并转向以记忆 T 细胞为主的寡克隆池,从而导致老年人群对新感染和疫苗的反应较差,因此预防和/或逆转胸腺萎缩是有效的。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。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。 ,胸腺功能的保存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,过氧化氢酶的缺乏对基质萎缩有深刻的影响。 (猫),它负责正常有氧代谢过程中产生的活性氧(ROS)的最终解毒,补充这种缺陷可以减轻胸腺萎缩,我们建议测试终生补充抗氧化活性是否可以延长重要的胸腺基质功能和功能。由于这些研究的潜在结果是治疗性的,因此我们还进行了一些实验来确定为什么 ROS 对基质细胞的多种生理功能有用。 ROS 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抗原 (TRA) 基因表达至关重要。因此,为了诱导中枢耐受,我们还将测试 ROS 诱导的应激与自噬诱导之间的关系,因为它与自身抗原呈递和耐受有关,所提出的研究旨在全面评估其有效性和可行性。利用抗氧化活性随着年龄的增长延长免疫功能,同时 揭示胸腺生物学和病理学的新机制。

项目成果

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Ann Venables Griffith其他文献

Ann Venables Griffith的其他文献

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{{ truncateString('Ann Venables Griffith', 18)}}的其他基金

Development of a socio-ecological model of wellness and resilience support
开发健康和复原力支持的社会生态模型
  • 批准号:
    10810518
  • 财政年份:
    2023
  • 资助金额:
    $ 5.9万
  • 项目类别:
The role of medullary thymic epithelial cell-derived growth factors in regulating thymus growth and atrophy
胸腺髓质上皮细胞源性生长因子在调节胸腺生长和萎缩中的作用
  • 批准号:
    10648448
  • 财政年份:
    2023
  • 资助金额:
    $ 5.9万
  • 项目类别:
Science as a Team Sport: Leveling the playing field and setting the rules of engagement.
科学作为一项团队运动:公平竞争环境并制定参与规则。
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    10810524
  • 财政年份:
    2023
  • 资助金额:
    $ 5.9万
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IMSD at UT Health San Antonio
UT Health San Antonio 的 IMSD
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    10571554
  • 财政年份:
    2023
  • 资助金额:
    $ 5.9万
  • 项目类别:
The impact of aging and thymus regeneration on tissue-resident CD8 T cell responses to viral lung infection and vaccination
衰老和胸腺再生对组织驻留 CD8 T 细胞对病毒肺部感染和疫苗接种反应的影响
  • 批准号:
    10527615
  • 财政年份:
    2022
  • 资助金额:
    $ 5.9万
  • 项目类别:
The impact of aging and thymus regeneration on tissue-resident CD8 T cell responses to viral lung infection and vaccination
衰老和胸腺再生对组织驻留 CD8 T 细胞对病毒肺部感染和疫苗接种反应的影响
  • 批准号:
    10626149
  • 财政年份:
    2022
  • 资助金额:
    $ 5.9万
  • 项目类别:
The role of paracrine mTOR signaling in regulating thymus size and function
旁分泌 mTOR 信号在调节胸腺大小和功能中的作用
  • 批准号:
    10352460
  • 财政年份:
    2021
  • 资助金额:
    $ 5.9万
  • 项目类别:
Causes and consequences of declining B cell-mediated central T cell tolerance throughout the lifespan
B 细胞介导的中枢 T 细胞耐受性在整个生命周期中下降的原因和后果
  • 批准号:
    10393822
  • 财政年份:
    2021
  • 资助金额:
    $ 5.9万
  • 项目类别:
The role of paracrine mTOR signaling in regulating thymus size and function
旁分泌 mTOR 信号在调节胸腺大小和功能中的作用
  • 批准号:
    10218405
  • 财政年份:
    2021
  • 资助金额:
    $ 5.9万
  • 项目类别:
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:
    9902004
  • 财政年份:
    2016
  • 资助金额:
    $ 5.9万
  • 项目类别:

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