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Molecular basis for age-related thymic involution and rejuvenation

与年龄相关的胸腺复旧和复兴的分子基础

基本信息

批准号：
8610399
负责人：
DONG-MING SU
金额：
$ 4.8万
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：
2009-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610399
关键词：
Adult Affect Age Aging Alleles Animals Apoptosis Autoantigens Autoimmune Process Autoimmunity Boxing CMV promoter Cell Differentiation process Cell physiology Cellular Immunity Complementary DNA Deterioration Development Elderly Elements Embryo Epithelial Cells Excision Fetal Thymic Organ Culture Functional disorder Future Gene Expression Generations Genes Genetic Growth Factor Human Immune system Immunity Infection prevention Interleukin-2 Knockout Mice LacZ Genes Ligands Longevity Lymphopoiesis Maintenance Maps Mediating Modeling Molecular Mus Mutation Natural regeneration Nude Mice Organogenesis Pathway interactions Peripheral Phenotype Prevention RNA Regulation Regulator Genes Regulatory T-Lymphocyte Rejuvenation Rodent Role Sorting - Cell Movement Stromal Cells T-Cell Immunodeficiency T-Lymphocyte Terminator Codon Testing Thymic epithelial cell Thymocyte Development Thymus Gland Time Tissues Transgenic Mice Undifferentiated Up-Regulation adaptive immunity age related antibiotic G 418 base central tolerance gain of function immunosenescence improved loss of function middle age migration mouse model notch protein novel postnatal prevent thymocyte tool

项目摘要

DESCRIPTION (provided by applicant): This proposal will identify molecular changes that maintain the thymic microenvironment, deterioration of which is believed to cause age-related thymic involution. Thymic epithelial cells (TEC) constitute a major element of the thymic microenvironment that directs thymocyte development and controls key thymic functions that generate and maintain effective adaptive immunity to infection, and prevent development of autoimmunity. TEC differentiation requires the epithelial cell-autonomous gene forkhead box N1 (Foxn1). Several inborn Foxn1 mutations have provided information on mechanisms by which Foxn1 regulates TEC function during thymic organogenesis in the embryos. However, the function of Foxn1 in the mature thymus and in natural thymic aging is unclear. We have generated a Foxn1fx mouse, which permits conditional deletion of Foxn1 temporally and allows us to study the role of Foxn1 in functional maintenance of the postnatal thymus and age-related thymic involution. We will test the hypothesis that Foxn1-controlled TECs mediate critical changes of thymic aging, including T-lymphopoiesis and prevention of autoimmunity. To test this hypothesis, we propose four specific aims. 1) We will identify TEC subpopulations that are most sensitive to loss of Foxn1 by evaluating TEC phenotypes after rapid deletion of Foxn1 and during spontaneous and gradual excision of Foxn1, determine TEC-derived T-cell growth factors, including expression of Notch ligands. We will also determine if removal of Foxn1 affects thymocyte phenotypes, T-cell apoptosis. We will conditionally supply exogenous Foxn1 in the middle-aged mice to test if it delays age-related thymic insufficiency. 2) We will elucidate the mechanisms by which conditional Foxn1 deletion in the postnatal thymus causes the TEC phenotypes identified in aim 1, such as enhanced apoptosis and reduced expression of Notch ligands. 3) We will determine if the increased autoimmunity in aging is related to loss of Foxn1 function, and resulting reduced medullary TEC (mTEC) function. In the conditional Foxn1-deleted mice, we will evaluate mTEC differentiation and expression of genes associated with development of central tolerance in the postnatal thymus, as well as regulatory T-cell function. 4). We will map Foxn1-regulated molecules at transcriptional level by obtaining TECs from mice with deleted Foxn1, normal Foxn1, and normal-then-off Foxn1 expression, based on generation of a Foxn1geo gene-trap mouse model. RNA from TECs will be hybridized to microarrays to identify possible mechanisms and pathways by which Foxn1 regulates TEC development. These studies will provide critical new information on the molecular basis for age-related thymic involution and rejuvenation, and lay the groundwork for future studies to preserve or regenerate thymic function and to maintain T-cell immunity in the elderly. Molecular basis for age-related thymic involution and rejuvenation Narrative for the proposal: The thymic microenvironment is mainly controlled by the states of thymic epithelial cells, which are regulated by Foxn1 gene. We have developed a novel mouse model in which the Foxn1 gene can be temporally deleted, which provides a powerful tool to study the mechanisms of postnatal thymic involution, thymic insufficiency-derived immunosenescence, and the increased autoimmunity in aging. These studies will lay the groundwork for restoring thymic dysfunction and extending the functional lifespan of human cellular immunity.

描述（由申请人提供）：该提案将鉴定维持胸腺微环境的分子变化，其恶化被认为会导致与年龄相关的胸腺退化。胸腺上皮细胞（TEC）构成胸腺微环境的主要元素，指导胸腺细胞发育并控制关键胸腺功能，从而产生和维持针对感染的有效适应性免疫，并防止自身免疫的发展。 TEC 分化需要上皮细胞自主基因叉头框 N1 (Foxn1)。一些先天性 Foxn1 突变提供了有关 Foxn1 在胚胎胸腺器官发生过程中调节 TEC 功能的机制的信息。然而，Foxn1 在成熟胸腺和自然胸腺衰老中的功能尚不清楚。我们培育了一只 Foxn1fx 小鼠，它允许暂时有条件地删除 Foxn1，并允许我们研究 Foxn1 在出生后胸腺功能维持和与年龄相关的胸腺复旧中的作用。我们将验证 Foxn1 控制的 TEC 介导胸腺衰老的关键变化（包括 T 淋巴细胞生成和预防自身免疫）的假设。为了检验这一假设，我们提出了四个具体目标。 1) 我们将通过评估快速删除 Foxn1 后以及自发和逐渐切除 Foxn1 期间的 TEC 表型，确定对 Foxn1 丢失最敏感的 TEC 亚群，确定 TEC 衍生的 T 细胞生长因子，包括 Notch 配体的表达。我们还将确定 Foxn1 的去除是否会影响胸腺细胞表型和 T 细胞凋亡。我们将有条件地向中年小鼠提供外源性Foxn1，以测试它是否可以延缓与年龄相关的胸腺功能不全。 2) 我们将阐明出生后胸腺中条件性 Foxn1 缺失导致目标 1 中确定的 TEC 表型的机制，例如细胞凋亡增强和 Notch 配体表达减少。 3) 我们将确定衰老过程中自身免疫性的增加是否与 Foxn1 功能丧失以及由此导致的髓质 TEC (mTEC) 功能降低有关。在条件性 Foxn1 缺失小鼠中，我们将评估 mTEC 分化和与出生后胸腺中枢耐受性发展相关的基因表达，以及调节性 T 细胞功能。 4).基于 Foxn1geo 基因陷阱小鼠模型的生成，我们将通过从 Foxn1 缺失、正常 Foxn1 和正常后关闭 Foxn1 表达的小鼠获得 TEC，在转录水平上绘制 Foxn1 调节分子图谱。来自 TEC 的 RNA 将与微阵列杂交，以确定 Foxn1 调节 TEC 发育的可能机制和途径。这些研究将为与年龄相关的胸腺退化和再生的分子基础提供重要的新信息，并为未来研究保留或再生胸腺功能以及维持老年人的T细胞免疫奠定基础。与年龄相关的胸腺退化和返老还童的分子基础提案叙述：胸腺微环境主要受胸腺上皮细胞状态控制，而胸腺上皮细胞受 Foxn1 基因调控。我们开发了一种新的小鼠模型，其中 Foxn1 基因可以暂时删除，这为研究出生后胸腺复旧、胸腺功能不全衍生的免疫衰老以及衰老过程中自身免疫增强的机制提供了有力的工具。这些研究将为恢复胸腺功能障碍和延长人类细胞免疫的功能寿命奠定基础。