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：
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
项目类别：
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

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反应的关键介质，但它们会不断丢失在整个生命周期中，因此胸腺是新 T 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，结果是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感染，尤其是流感等病毒感染。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。控制胸腺萎缩的机制很难确定，因为萎缩的主要目标，皮质胸腺基质细胞很少且难以分离，为了了解这些机制，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在最近发表的一项研究中，我们表明皮质胸腺会萎缩或实验诱导再生。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 数量在萎缩期间不会减少，在再生期间会增加，相反，这些动态过程。进一步的信息分析表明，cTEC 大小和分支形态的变化似乎受到调节。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。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。