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lymphostromal interactions in the thymic aging

胸腺衰老过程中淋巴基质的相互作用

基本信息

批准号：
8183846
负责人：
DONG-MING SU
金额：
$ 12.91万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8183846
关键词：
Affect Age Age-Months Aging Animals Atrophic Birth Bone Marrow Transplantation Cell Aging Cell Line Cells Chimera organism Complex Data Defect Development Elderly Failure Functional disorder Gene Targeting Genes Hematopoietic stem cells Human IL7R gene Immune system In Situ Hybridization Injection of therapeutic agent Interleukin-7 Kidney Life Ligands Longevity Lymphoid Lymphopoiesis Measures Mediating Modeling Multipotent Stem Cells Mus Natural regeneration Peripheral Publishing Reporting Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Sorting - Cell Movement Staging Stem Cell Factor Stem cells Stromal Cells T-Cell Development T-Cell Receptor T-Lymphocyte Testing Thymic epithelial cell Thymus Gland Time Transplantation age related aged base capsule cell age combat cytokine exhaust fetal immunosenescence improved in vivo intravenous administration juvenile animal middle age muscle aging notch protein progenitor public health relevance research study thymocyte

项目摘要

DESCRIPTION (provided by applicant): Aging causes thymic involution which decreases thymic lymphopoiesis and exhausts the naive T-cell pool, constricting diversity of T-cell receptor repertoire and inducing immunosenescence. However, the mechanisms related to cellular compartments underlying thymic involution are unclear. The two main cellular compartments in the thymus are lymphohematopoietic progenitor cells (LPCs) and thymic epithelial cells (TECs). Currently, it is controversial if LPCs develop a cumulative intrinsic defect with age to trigger thymic involution, or whether aging results in dysfunction of TECs, causing secondary changes in thymocytes and thymic involution. Based on our preliminary studies, we hypothesize that the primary/dominant defect in aging is dysfunction of TECs, which in turn causes age-related thymopoietic insufficiency, in part through inadequate Notch gene signals that affect early stages of T-cell development. We will test these hypotheses through the following specific aims: 1). Compare the capacity of LPCs from middle-aged/aged and young animals to competitively develop in thymic stromal niches of young animals. We will measure competitive repopulation of unirradiated young IL-7R-/- recipient thymi by LPCs from old and young mice, to determine if the former have any intrinsic and irreversible defects. We will use a second competitive model, transplanting a fetal TEC network from RAG-/- mice to the kidney capsule of young RAG-/- mice, followed by intravenous administration of LPCs from old and young mice. 2). To determine whether the thymic microenvironment in aging provides inadequate Notch signals, resulting in reduced thymic lymphopoiesis. We will analyze expression of Notch ligands in TECs, and Notch receptors and Notch target genes in early stage thymocytes from aged mice. Then, we will provide enhanced Notch signaling to aged thymus in vivo by infusing Notch ligand-expressing thymic epithelial cell lines. We will then determine whether the enhanced Notch signaling can improve early stages of T-cell development in the aged thymus. The proposed studies will improve our understanding of the mechanism(s) of aging-related decreased T-lymphopoiesis and lay the groundwork for development of practical strategies to combat thymopoietic failure due to aging. PUBLIC HEALTH RELEVANCE: This proposal will identify the cellular compartment which has the dominant/primary defect that causes aging-related thymic involution, and determine whether inadequate Notch signals contribute to this defect by impairing early T-cell development and T-lymphopoiesis in the elderly.

描述（由申请人提供）：衰老导致胸腺退化，减少胸腺淋巴生成，耗尽幼稚t细胞库，收缩t细胞受体库的多样性，诱导免疫衰老。然而，与胸腺退化的细胞区室相关的机制尚不清楚。胸腺的两个主要细胞区室是淋巴造血祖细胞（LPCs）和胸腺上皮细胞（TECs）。目前，对于LPCs是否随着年龄的增长而产生累积的内在缺陷从而引发胸腺退化，还是衰老导致tec功能障碍，导致胸腺细胞继发性改变和胸腺退化存在争议。根据我们的初步研究，我们假设衰老的主要/主要缺陷是tec功能障碍，这反过来导致与年龄相关的胸腺功能不全，部分原因是Notch基因信号不足影响了t细胞发育的早期阶段。我们将通过以下具体目标来检验这些假设：1)。比较中老年动物和幼龄动物的LPCs在幼龄动物胸腺基质生态位竞争性发育的能力。我们将通过来自老年和年轻小鼠的LPCs测量未照射的年轻IL-7R-/-受体胸腺的竞争性繁殖，以确定前者是否有任何内在的和不可逆转的缺陷。我们将使用第二种竞争模型，将来自RAG-/-小鼠的胎儿TEC网络移植到年轻RAG-/-小鼠的肾包膜中，然后静脉注射来自老年和年轻小鼠的LPCs。2)。确定衰老时胸腺微环境是否提供了不足的Notch信号，从而导致胸腺淋巴生成减少。我们将分析Notch配体在tec中的表达，以及Notch受体和Notch靶基因在老年小鼠早期胸腺细胞中的表达。然后，我们将通过注入表达Notch配体的胸腺上皮细胞系，在体内向衰老的胸腺提供增强的Notch信号。然后，我们将确定增强的Notch信号是否可以改善老年胸腺中t细胞发育的早期阶段。这些研究将提高我们对衰老相关的t淋巴细胞生成减少的机制的理解，并为开发对抗衰老引起的胸腺功能衰竭的实用策略奠定基础。公共卫生相关性：本提案将确定具有导致衰老相关胸腺退化的显性/原发性缺陷的细胞室，并确定Notch信号不足是否通过损害老年人早期t细胞发育和t淋巴生成而导致这种缺陷。