Causes and Consequences of Age-Induced Thymic Involution

描述（由申请人提供）：本申请的中心假设是胸腺退化是由骨髓T细胞前体、胸腺内祖细胞和胸腺间质细胞的年龄相关变化引起的。一个目标是定义和描述这些人群的内在影响。第二个目标是确定伴随生长激素（GH）和胰岛素样生长因子- i （IGF-I）的产生下降，以及性类固醇（可能导致胸腺细胞死亡）的产生增加，在青春期对骨髓和胸腺细胞的影响。Aim 1的研究将研究为什么来自老年小鼠的多能造血干细胞（PHSC）不能有效地产生T细胞，通过测试假设它们向共同淋巴样祖细胞（CLP）和/或更承诺的T细胞祖细胞的分化受到衰老的损害。此外，GH、IGF-I或性类固醇生成的年龄相关变化是否会影响PHSC和CLP区室的大小将被确定。目的2将研究衰老如何影响胸腺内祖细胞池。胸腺中最不成熟的CD44+CD25-前体以正常频率存在，但它们的成熟被阻断。研究将确定这是由于该种群积累的内在变化和/或影响其生长和生存的微环境和内分泌信号平衡的改变。最后，Aim 3将使用新开发的成人胸腺重组培养系统评估衰老是否以及如何影响胸腺基质细胞。此外，胎儿胸腺器官培养将用于模拟上述激素产生的年龄相关变化如何影响胸腺基质细胞支持T细胞发育的能力。综上所述，从这些研究中获得的信息将确定胸腺退化的基础，并在制定增强细胞介导免疫和使免疫功能低下个体胸腺恢复活力的策略方面具有价值。

DESCRIPTION (provided by applicant): The central hypothesis of this application is that thymic involution results from age-related changes in bone marrow T cell precursors, intrathymic progenitors, and thymic stromal cells. One aim is to define and characterize effects intrinsic to each of these populations. A second goal is to determine how concomitant declines in the production of Growth Hormone (GH) and Insulin-Like Growth Factor-I (IGF-I), which are thymopoietic, and increases in production of sex steroids, which potentiate thymocyte death, at puberty impact on cells in the bone marrow and thymus. Studies in Aim 1 will investigate why pluripotent hematopoietic stem cells (PHSC) from old mice do not efficiently generate T cells by testing the hypothesis that their differentiation into common lymphoid progenitors (CLP) and/or more committed T cell progenitors is compromised by aging. In addition, whether or not age-related changes in the production of GH, IGF-I or sex steroids affect the size of the PHSC and CLP compartments will be determined. Aim 2 will investigate how aging affects the pool of intrathymic progenitors. The most immature CD44+CD25- precursors in the thymus are present at a normal frequency but their maturation is blocked. Studies will determine whether this is due to intrinsic changes that accumulate in this population and/or to alterations in the balance of microenvironmental and endocrine signals that affect their growth and survival. Finally, Aim 3 will assess if and how aging affects thymic stromal cells using a newly developed, adult thymus reaggregate culture system. In addition, fetal thymic organ cultures will be used to model how age-related changes in hormone production noted above impact on the ability of thymic stromal cells to support T cell development. Taken together, the information obtained from these studies will define the basis for thymic involution and be of value in the formulation of strategies to boost cell-mediated immunity and rejuvenate the thymus in immunocompromised individuals.