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
• 负责人: Ann Venables Griffith
• 金额: $ 23.16万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-16 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218405
• 关键词: Age; Aging; Antibodies; Area; Atrophic; Automobile Driving; Biology; Cell Count; Cell Size; Cells; Cellular Morphology; Cellularity; Databases; Elderly; Etiology; FGF21 gene; FRAP1 gene; Functional disorder; Generations; Genes; Genetic; Genetic Transcription; IGF1 gene; Infection; Informatics; Label; Life; Ligands; Longevity; Mediator of activation protein; Memory; Modeling; Monitor; Morphology; Mus; Natural regeneration; Paracrine Communication; Pathway interactions; Phenotype; Phosphotransferases; Play; Population; Positioning Attribute; Process; Production; Promoter Regions; Publishing; Reporter; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Self Tolerance; Signal Transduction; Site; Stains; Stromal Cells; T cell differentiation; T memory cell; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Tissues; Transgenic Mice; Vaccines; Validation; Virus Diseases; adaptive immune response; age related; aging population; experience; flu; fusion gene; healthspan; insight; interest; mouse model; novel; overexpression; paracrine; prevent; response; transgene expression

Summary T lymphocytes are critical mediators of the adaptive immune response, however, they are continuously lost throughout the lifespan, and therefore must be continuously replaced. The thymus is the primary site of new T cell generation, and the unique thymic stromal microenvironment directs T cell differentiation, self-tolerance and self-restriction. However, the size of the thymus declines precipitously beginning relatively early in life, resulting in declining production of new, naïve T cells. As a result, homeostatic mechanisms driven expansion of memory cells in the periphery, driving a shift toward an oligoclonal T cell memory, leaving the elderly less responsive to vaccines and new infections, especially viral infections such as flu. Preventing or reversing age-associated thymic atrophy therefore hold great potential for extending the healthspan in the aging population. The mechanisms governing thymic atrophy have been difficult to identify, because the primary targets of atrophy, cortical thymic stromal cells, are rare and difficult to isolate. To understand these mechanisms, we have applied an informatic approach to characterize the transcriptional response of thymic stromal cells during age-related atrophy or experimentally induced regeneration. In a recently published study, we showed that cortical thymic epithelial cells (cTECs) display a unique morphology characterized by extensive looping projections, while atrophy is associated with by contraction of these projections, which are renewed during induced regeneration. In addition, we used a combination of genetic reporter models and biosynthetic labeling to show that cTEC numbers do not decrease during atrophy of increase during regeneration. Instead, these dynamic processes appear to be regulated by changes in cTEC size and branching morphology. Further informatic analysis indicated that paracrine signaling between medullary and cortical TEC, particularly involving the mammalian target of rapamycin (mTOR) pathway, was likely to play a key role in the mechanisms of atrophy and regeneration. We will test the hypothesis that paracrine mTOR signaling maintains thymus size using tissue-specific transgenic mice overexpressing mTOR activating ligands in medullary thymic epithelial cells (mTEC).

概括 T 淋巴细胞是适应性免疫反应的关键介质，但它们会不断丢失 在整个使用寿命期间，因此必须不断更换。胸腺是新T细胞的主要部位 细胞生成，独特的胸腺基质微环境指导 T 细胞分化、自我耐受和 自我限制。然而，胸腺的大小在生命相对较早的时候就开始急剧下降，导致 新的、幼稚的 T 细胞产量下降。结果，稳态机制驱动了记忆的扩展 外周细胞，推动向寡克隆 T 细胞记忆的转变，使老年人对 疫苗和新的感染，尤其是流感等病毒感染。预防或逆转与年龄相关的 因此，胸腺萎缩对于延长老年人口的健康寿命具有巨大的潜力。这 控制胸腺萎缩的机制很难确定，因为萎缩的主要目标， 皮质胸腺基质细胞罕见且难以分离。为了理解这些机制，我们应用了 一种表征年龄相关胸腺基质细胞转录反应的信息学方法 萎缩或实验诱导的再生。在最近发表的一项研究中，我们表明皮质胸腺 上皮细胞（cTEC）表现出独特的形态，其特征是广泛的环状投影，而 萎缩与这些突起的收缩有关，这些突起在诱导再生过程中被更新。 此外，我们结合使用遗传报告模型和生物合成标记来表明 cTEC 萎缩期间数量不会减少，再生期间数量会增加。相反，这些动态过程 似乎受到 cTEC 大小和分支形态变化的调节。进一步的信息分析表明 髓质和皮质 TEC 之间的旁分泌信号传导，特别是涉及哺乳动物的目标 雷帕霉素（mTOR）途径可能在萎缩和再生机制中发挥关键作用。我们 将使用组织特异性转基因检验旁分泌 mTOR 信号传导维持胸腺大小的假设 在胸腺髓质上皮细胞 (mTEC) 中过表达 mTOR 激活配体的小鼠。