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.

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。防止或逆转与年龄相关的胸腺萎缩 因此，在衰老人群中扩展健康状态有很大的潜力。控制机制 胸腺萎缩很难鉴定，因为萎缩，皮质胸腺基质的主要靶标 细胞，罕见且难以分离。为了了解这些机制，我们采用了一种有益的方法 表征在与年龄相关萎缩或实验中的胸腺基质细胞的转录反应 诱导的再生。我们发现髓质和皮质上皮细胞（TEC），旁分泌信号传导， 尤其涉及雷帕霉素（MTOR）途径的哺乳动物靶标，可能在 萎缩和再生的机制。要开发工具，需要测试MTEC衍生的假设 （特别是FGF21）促进胸腺的生长，并促进旁分泌的更广泛的机械研究 调节胸腺功能，我们最近确定了一个基因（LPO），该基因驱动麦克利在 胸腺中的大多数MTEC。在这里，我们提出了类似的敲入小鼠的生成，其中LPO驱动器 CRE重组酶的表达，允许组织特异性的MTEC遗传操纵。我们还将使用 新生成的模型使用FGF21LOXP小鼠研究了MTEC衍生的FGF21的作用。