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
• 负责人: Ann Venables Griffith
• 金额: $ 19.38万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10352460
• 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).

总结 T淋巴细胞是适应性免疫反应的关键介质，然而，它们不断地丢失 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 自我约束然而，胸腺的大小在生命的相对早期开始急剧下降， 减少新的幼稚T细胞的产生。结果，自我平衡机制驱动了记忆的扩展， 细胞在外周，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，特别是病毒感染，如流感。预防或逆转年龄相关 因此，胸腺萎缩在延长老龄人口的健康寿命方面具有很大的潜力。的 控制胸腺萎缩的机制一直难以确定，因为萎缩的主要靶点， 皮质胸腺基质细胞，是罕见的，难以分离。为了理解这些机制，我们应用了 一种信息学方法来表征胸腺基质细胞在年龄相关的转录反应 萎缩或实验诱导的再生。在最近发表的一项研究中，我们发现皮质胸腺 上皮细胞（cTEC）显示出独特的形态，其特征在于广泛的环状突起，而 萎缩与这些突起的收缩有关，这些突起在诱导再生期间更新。 此外，我们使用了遗传报告模型和生物合成标记的组合，以表明cTEC 数量在萎缩期间不减少，在再生期间增加。相反，这些动态过程 似乎是由cTEC的大小和分支形态的变化进行调节。进一步的信息分析表明， 髓质和皮质TEC之间的旁分泌信号，特别是涉及哺乳动物的靶点， 雷帕霉素（mTOR）通路的参与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技术检验旁分泌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活化配体的小鼠。