Molecular Mechanisms of Thymic Epithelial Cell Involution in Aging

描述（由申请人提供）：胸腺退化是免疫系统老化的标志。胸腺由胸腺上皮细胞（TECs）、成纤维细胞和血源性基质细胞组成。将年轻和年老的造血干细胞过继移植到年轻和年老的受者体内，可以得出这样的结论：老年人的胸腺功能受损主要是老年胸腺微环境的结果。TEC的分化、增殖和存活受细胞内外因素的控制。尽管很多工作都集中在胚胎发生过程中胸腺的发育，但相对而言，对胸腺退化的机制知之甚少。这尤其与tec有关，我们假设tec是衰老过程中胸腺生成的主要障碍。我们现在建议填补这一关键空白。我们的具体目标是：目的1：确定老化影响tec的关键转录因子和信号通路。在目的1A中，我们将探讨老年和年轻TEC亚群的生理特征。在aim 1B中，我们假设调节胸腺发育的关键细胞表面受体和细胞内转录途径对老年小鼠基因毒性应激后TEC的维持和再生很重要。在aim 1C中，我们假设微rna的转录调控是TEC衰老的重要组成部分。单独研究tec的功能丧失将在目标1B和1C中进行。目的2：验证衰老过程扰动的遗传模型将为TEC衰老机制提供关键见解的假设。我们将确定影响按时间顺序衰老的小鼠和过早衰老的小鼠之间tec的共同特征，并在延迟胸腺衰老模型中区分特征。如前所述，刺激TEC的药物可作为评估衰老过程中TEC功能残留的探针。

DESCRIPTION (provided by applicant): Thymic involution constitutes a hallmark of an aging immune system. The thymus is comprised of thymic epithelial cells (TECs), fibroblasts and blood-borne stromal cells. Adoptive transfers of young and old hematopoietic stem cells into young vs old recipients has led to the conclusion that impaired thymopoiesis in the aged is largely the consequence of an aged thymic microenvironment. TEC differentiation, proliferation, and survival are controlled by cell intrinsic and extrinsic factors. Although much work has been focused on thymus development during embryogenesis, comparatively little is known about the mechanisms responsible for thymic involution. This especially pertains to TECs, which we hypothesize are the major impediment to thymopoiesis during aging. We now propose to fill this critical gap. Our specific aims are: Aim 1: To determine the key transcription factors & signaling pathways in TECs affected by aging. In aim 1A, we will interrogate physiological characteristics of aged vs young TEC subsets. In aim 1B, we hypothesize that key cell surface receptor and intracellular transcriptional pathways that regulate thymic development will be important for TEC maintenance and regeneration after genotoxic stress in aged mice. In aim 1C, we hypothesize that transcriptional regulation by micro-RNAs is an important component of TEC aging. Studies of loss-of-function in TECs alone will be performed in aims 1B and 1C. Aim 2: To test the hypothesis that genetic models of perturbations of the aging process will provide key insights as to the mechanisms responsible for TEC aging. We will identify common features affecting TECs between chronologically aged mice and those with premature aging and distinguishing features in a model of delayed thymic aging. As indicated, drugs that stimulate TECs as probes for assessing residual TEC function in aging.