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
• 负责人: Ann Venables Griffith
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10648448
• 关键词: Ablation; Age; Aging; Alleles; Antibodies; Area; Atrophic; Automobile Driving; Biology; CRISPR/Cas technology; Candidate Disease Gene; Cells; Cellularity; Complementary DNA; Databases; Elderly; Enterobacteria phage P1 Cre recombinase; Epithelial Cells; Exons; FGF3 gene; FRAP1 gene; Flow Cytometry; Generations; Genes; Genetic Models; Genetic Recombination; Genetic Transcription; Growth; Growth Factor; Immunofluorescence Microscopy; Infection; Informatics; Knock-in; Knock-in Mouse; Life; Longevity; Maintenance; Measures; Mediating; Mediator; Memory; Modeling; Molecular; Monitor; Mouse Strains; Mus; Natural regeneration; Newborn Infant; Paracrine Communication; Pathway interactions; Phenotype; Phosphotransferases; Play; Population; Production; Publishing; Regulation; Reporter Genes; Research Design; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Self Tolerance; Signal Pathway; Signal Transduction; Site; Stains; Stromal Cells; Structure of thymic cortex; T cell differentiation; T memory cell; T-Cell Development; T-Lymphocyte; Tamoxifen; Testing; Thymic epithelial cell; Thymus Gland; Tissues; Transgenic Organisms; Vaccines; Validation; Virus Diseases; Wild Type Mouse; adaptive immune response; age related; aging population; candidate identification; cell type; experimental study; fetal; fibroblast growth factor 21; genetic manipulation; healthspan; interest; mouse model; paracrine; prevent; receptor; response; tool

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. 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. We found that paracrine signaling between medullary and cortical epithelial cells (TECs), particularly involving the mammalian target of rapamycin (mTOR) pathway, was likely to play a key role in the mechanisms of atrophy and regeneration. To develop tools required test the hypothesis mTEC-derived signals (particularly FGF21) promote thymus growth, and to facilitate more extensive mechanistic studies of paracrine regulation of thymus function, we recently identified a gene (LPO) that drives specific expression of mCherry in most mTEC within the thymus. Here, we propose the generation of similar knock-in mice in which LPO drives expression of Cre recombinase, allowing tissue-specific genetic manipulation of mTECs. We will also use the newly generated model to investigate the role of mTEC-derived FGF21 using FGF21LoxP mice.

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。预防或逆转与年龄相关的胸腺萎缩 因此，在延长老龄人口的健康寿命方面具有很大的潜力。管理机制 胸腺萎缩一直难以确定，因为萎缩的主要目标，皮质胸腺间质 细胞，是罕见的，难以分离。为了理解这些机制，我们采用了信息学方法 为了表征胸腺基质细胞在年龄相关性萎缩期间的转录反应， 诱导再生我们发现髓质和皮质上皮细胞（TEC）之间的旁分泌信号， 特别是涉及雷帕霉素（mTOR）通路的哺乳动物靶蛋白，很可能在 萎缩和再生的机制。开发测试mTEC衍生信号假设所需的工具 （特别是FGF 21）促进胸腺生长，并促进更广泛的旁分泌机制的研究， 调节胸腺功能，我们最近确定了一个基因（LPO），驱动mCherry的特异性表达， 大多数mTEC在胸腺内。在这里，我们提出了类似的基因敲入小鼠，其中LPO驱动 Cre重组酶的表达，允许mTEC的组织特异性遗传操作。我们还将使用 使用FGF21LoxP小鼠研究mTEC衍生的FGF21的作用的新产生的模型。