Thymic adipogenesis and age-related thymic demise

胸腺脂肪生成和与年龄相关的胸腺死亡

基本信息

批准号：
8818658
负责人：
VISHWA DEEP DIXIT
金额：
$ 41.63万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-01 至 2018-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8818658
关键词：
Ablation Address Adipocytes Adipose tissue Adult Age Aging Aging-Related Process Biological Models Blood capillaries Calories Cell Lineage Cell physiology Cells Clinical Cues Data Deterioration Development Elderly Emigrations Employee Strikes Endothelial Cells Environment Epithelial Etiology Event Excision Fatty Change Fibroblasts Functional disorder Generations Genes Goals Health Hematopoietic Homeostasis Immune Immune System Diseases Immunity Immunology Infection Label Lead Life Lipids Lymphopoiesis Malignant Neoplasms Membrane Mesenchymal Mus Obesity Peroxisome Proliferator-Activated Receptors Process Production Proteins Reporter Research Research Project Grants Signal Transduction Stromal Cells T-Cell Development T-Lymphocyte Testing Thymic epithelial cell Thymus Gland Time Tracer Transgenic Organisms Vacuole adipocyte differentiation age related base capillary cell type chemokine design fibrogenesis fighting immune function in vivo lipid biosynthesis middle age novel novel strategies novel therapeutic intervention prevent progenitor public health relevance research study thymocyte transcription factor venule

项目摘要

DESCRIPTION (provided by applicant): Diminished ability of thymus to produce naive T cells with progressive aging remains a fundamental and puzzling phenomenon for immunology and to-date, an intractable clinical condition that contributes to immune dysfunction in elderly. With advancing age, the thymus undergoes striking fibrotic and fatty changes that culminate in its transformation into adipose tissue. The lineage of ectopic adipocytes and the mechanism of development of thymic adipocytes during aging are not well understood. Using lineage-tracing, our research team has shown that FoxN1+ thymic epithelial cells (TECs), that are necessary for T cell development, can transition and give rise to thymic adipogenic precursors. Consistent with this new paradigm, our lates preliminary data provide further in vivo evidence that proadipogenic cells in aging thymus can originate from epithelial and endothelial lineages via a secondary mesenchymal precursor. Based on our novel findings, the central hypothesis of this proposal is that the transition of TECs and endothelial cells contribute towards the lineage of thymic adipocytes and leads to age-related thymic involution. The corollary is that blocking the fibrogenesis and pro- adipogenic signaling in TEC and endothelial lineage cells will protect against aging of thymus. Experiments in Aim 1 will test the hypothesis 1 that with advancing age transition of FoxN1+ cells into adipogenic precursors via epithelial-mesenchymal transition (EMT) process gives rise to ectopic thymic adipocytes and compromises the thymic stromal microenvironment. Aim 2 will test the hypothesis 2 that that endothelial-lineage cells serve as adipogenic progenitors and will reveal that blocking he ectopic adipocyte development in thymic perivascular space protect against thymic aging. The Aim 3 will test the hypothesis 3 that age-related fibrogenesis in thymus causes reduction in thymopoiesis and reveal that mechanisms that commit secondary mesenchymal cells into adipocytes participate in thymic dysfunction. The long-term goal of this research project is to understand the mechanisms that cause thymic adiposity and to develop new approaches to prevent or reverse the process of age-related thymic involution.

描述（由申请人提供）：随着年龄的增长，胸腺产生幼稚 T 细胞的能力下降，这对于免疫学来说仍然是一个基本且令人费解的现象，迄今为止，这是一种导致老年人免疫功能障碍的棘手临床病症。随着年龄的增长，胸腺会经历显着的纤维化和脂肪变化，最终转变为脂肪组织。异位脂肪细胞的谱系和衰老过程中胸腺脂肪细胞的发育机制尚不清楚。通过谱系追踪，我们的研究团队表明，T 细胞发育所必需的 FoxN1+ 胸腺上皮细胞 (TEC) 可以转变并产生胸腺脂肪形成前体。与这一新范式一致，我们最新的初步数据提供了进一步的体内证据，表明衰老胸腺中的促脂肪细胞可以通过次级间充质前体起源于上皮和内皮谱系。基于我们的新发现，该提案的中心假设是 TEC 和内皮细胞的转变有助于胸腺脂肪细胞的谱系，并导致与年龄相关的胸腺退化。推论是阻断 TEC 和内皮谱系细胞中的纤维发生和促脂肪生成信号将防止胸腺衰老。目标 1 中的实验将检验假设 1，即随着年龄的增长，FoxN1+ 细胞通过上皮间质转化 (EMT) 过程转变为脂肪形成前体，产生异位胸腺脂肪细胞并损害胸腺基质微环境。目标 2 将检验假设 2，即内皮谱系细胞充当脂肪形成祖细胞，并将揭示阻断胸腺血管周围空间异位脂肪细胞的发育可防止胸腺衰老。目标 3 将检验假设 3，即胸腺中与年龄相关的纤维生成导致胸腺生成减少，并揭示将次级间充质细胞转化为脂肪细胞的机制参与胸腺功能障碍。该研究项目的长期目标是了解导致胸腺肥胖的机制，并开发新方法来预防或逆转与年龄相关的胸腺退化过程。