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

基本信息

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
项目类别：
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

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. 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，特别是病毒感染，预防或逆转与年龄相关的胸腺萎缩。因此，对于延长老龄化人口的健康寿命具有巨大的潜力。胸腺萎缩一直难以识别，因为萎缩的主要目标是皮质胸腺基质为了理解这些机制，我们采用了信息学方法。表征年龄相关性萎缩期间胸腺基质细胞的转录反应或实验我们发现髓质和皮质上皮细胞（TEC）之间的旁分泌信号传导，特别是涉及哺乳动物雷帕霉素靶点（mTOR）通路，可能在为了开发工具，需要测试 mTEC 衍生信号的假设。（特别是 FGF21）促进胸腺生长，并促进更广泛的旁分泌机制研究胸腺功能的调节，我们最近发现了一个基因（LPO），它驱动mCherry在在这里，我们建议生成类似的由 LPO 驱动的敲入小鼠。 Cre 重组酶的表达，允许对 mTEC 进行组织特异性遗传操作。新生成的模型使用 FGF21LoxP 小鼠研究 mTEC 衍生的 FGF21 的作用。