lymphostromal interactions in the thymic aging

胸腺衰老过程中淋巴基质的相互作用

• 批准号: 7846800
• 负责人: DONG-MING SU
• 金额: $ 4.43万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846800
• 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

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）：衰老会导致胸腺退化，从而减少胸腺淋巴细胞生成并耗尽幼稚 T 细胞库，限制 T 细胞受体库的多样性并诱导免疫衰老。然而，与胸腺复旧的细胞区室相关的机制尚不清楚。胸腺中的两个主要细胞区室是淋巴造血祖细胞（LPC）和胸腺上皮细胞（TEC）。目前，LPCs是否随着年龄的增长而产生累积的内在缺陷以触发胸腺复旧，或者衰老是否导致TECs功能障碍，引起胸腺细胞的继发性变化和胸腺复旧，仍存在争议。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，这反过来又导致与年龄相关的胸腺生成不足，部分原因是影响 T 细胞发育早期阶段的 Notch 基因信号不足。我们将通过以下具体目标来检验这些假设：1）。比较中年/老年和幼龄动物的 LPC 在幼龄动物胸腺基质生态位中竞争性发育的能力。我们将测量年老和年轻小鼠的 LPC 对未照射的年轻 IL-7R-/- 受体胸腺的竞争性再增殖，以确定前者是否存在任何内在的和不可逆的缺陷。我们将使用第二种竞争模型，将 RAG-/- 小鼠的胎儿 TEC 网络移植到年轻 RAG-/- 小鼠的肾囊，然后静脉注射来自年老和年轻小鼠的 LPC。 2）。确定衰老过程中胸腺微环境是否提供不足的 Notch 信号，从而导致胸腺淋巴细胞生成减少。我们将分析 TEC 中 Notch 配体的表达，以及老年小鼠早期胸腺细胞中 Notch 受体和 Notch 靶基因的表达。然后，我们将通过输注表达 Notch 配体的胸腺上皮细胞系，在体内向衰老胸腺提供增强的 Notch 信号传导。然后我们将确定增强的 Notch 信号传导是否可以改善衰老胸腺中 T 细胞发育的早期阶段。拟议的研究将提高我们对与衰老相关的 T 淋巴细胞生成减少机制的理解，并为制定对抗衰老导致的胸腺生成衰竭的实用策略奠定基础。公共健康相关性：该提案将确定具有导致与衰老相关的胸腺复旧的显性/主要缺陷的细胞区室，并确定Notch信号不足是否通过损害老年人的早期T细胞发育和T淋巴细胞生成而导致这种缺陷。