Molecular Mechanisms of Thymic Epithelial Cell Involution in Aging

描述（由申请方提供）：胸腺退化是免疫系统老化的标志。胸腺由胸腺上皮细胞（TEC）、成纤维细胞和血源性基质细胞组成。将年轻和老年造血干细胞连续转移到年轻与老年受者中已经得出结论，老年人中受损的胸腺生成在很大程度上是老年胸腺微环境的结果。TEC的分化、增殖和存活受到细胞内在和外在因素的控制。虽然许多工作都集中在胸腺发育在胚胎发生，相对较少的是知道胸腺退化的机制。这特别适用于TEC，我们假设这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：确定衰老影响TECs的关键转录因子和信号通路。在目标1A中，我们将询问老年与年轻TEC子集的生理特征。在目标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遗传毒性应激后TEC的维持和再生至关重要。在目标1C中，我们假设微RNA的转录调控是TEC老化的重要组成部分。将在目标1B和1C中单独进行TEC功能丧失研究。目标二：为了检验假设，即衰老过程的遗传扰动模型将提供关键的见解，负责TEC老化的机制。我们将确定共同的特点，影响TEC之间的时间老化的小鼠和那些过早老化和区别特征的模型延迟胸腺老化。如所指出的，刺激TEC的药物作为用于评估老化中残留TEC功能的探针。

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.