Causes and Consequences of Age-Induced Thymic Involution

年龄引起的胸腺退化的原因和后果

• 批准号: 6757210
• 负责人: KENNETH Allan DORSHKIND
• 金额: $ 26.26万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6757210
• 关键词: CD44 molecule; T lymphocyte; aging; bone marrow; cell age; cell differentiation; cell growth regulation; cytokine; flow cytometry; hematopoietic stem cells; hormone biosynthesis; hormone regulation /control mechanism; insulinlike growth factor; laboratory mouse; leukocyte activation /transformation; polymerase chain reaction; somatotropin; steroid hormone; thymus disorder; tissue /cell culture

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.

描述（由申请人提供）：本申请的中心假设是胸腺退化由骨髓T细胞前体、胸腺内祖细胞和胸腺基质细胞的年龄相关变化引起。目的之一是界定和描述这些人群中每一个人的内在效应。第二个目标是确定在青春期，生长激素（GH）和胰岛素样生长因子-I（IGF-I）（它们是胸腺生成的）的产生的伴随下降以及性类固醇（它们增强胸腺细胞死亡）的产生的增加如何影响骨髓和胸腺中的细胞。目的1中的研究将通过测试衰老损害了多能造血干细胞（PHSC）分化为普通淋巴祖细胞（CLP）和/或更定型的T细胞祖细胞的假设来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。此外，是否年龄相关的生长激素，IGF-I或性类固醇的生产变化影响PHSC和CLP室的大小将被确定。目的2将探讨衰老如何影响胸腺内祖细胞库。胸腺中最不成熟的CD 44 + CD 25-前体以正常频率存在，但其成熟被阻断。研究将确定这是否是由于在这一人群中积累的内在变化和/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，目标3将评估是否以及如何老化影响胸腺基质细胞使用新开发的，成人胸腺再聚集培养系统。此外，胎儿胸腺器官培养物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。总之，从这些研究中获得的信息将定义胸腺退化的基础，并在制定战略，以提高细胞介导的免疫和免疫功能低下的个人恢复胸腺的价值。