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

基本信息

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
项目类别：
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

项目摘要

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响应的关键介质，但是它们不断丢失通过寿命，因此必须连续更换。胸腺是新T的主要位置细胞产生，独特的胸腺基质微环境指导T细胞分化，自我耐受性和自我限制。但是，胸腺的大小在生命的早期就相对较早开始，结果在新的，幼稚的T细胞的产生下降。结果，体内稳态机制驱动了记忆的扩展周围的细胞，向寡克隆T细胞的记忆转移，使较低的响应能力较少疫苗和新感染，尤其是病毒感染，例如流感。防止或逆转与年龄相关的因此，胸腺萎缩具有扩展衰老人群中健康状态的巨大潜力。这控制胸腺萎缩的机制很难识别，因为萎缩的主要靶标，皮质胸腺基质细胞罕见且难以分离。要了解这些机制，我们已经应用了一种有益的方法来表征年龄相关期间胸腺基质细胞的转录反应萎缩或实验诱导的再生。在最近发表的研究中，我们表明了皮质胸腺上皮细胞（CTEC）表现出独特的形态，其特征是广泛的循环项目，而萎缩与这些项目的收缩有关，这些项目在诱导的再生过程中会更新。此外，我们使用了遗传报告基因模型和生物合成标记的组合来表明CTEC 在再生期间萎缩期间的数字不会减少。相反，这些动态过程似乎受CTEC大小和分支形态的变化调节。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，特别是涉及的哺乳动物靶标雷帕霉素（MTOR）途径可能在萎缩和再生机理中起关键作用。我们将检验以下假设：旁分泌MTOR信号传导使用组织特异性转基因维持胸腺大小过表达MTOR的小鼠在髓质胸腺上皮细胞（MTEC）中激活配体。