Effects of p16Ink4a and Arf on T Lineage Aging

描述（由申请方提供）：骨髓和胸腺中的T细胞前体发生与年龄相关的发育潜能下降，导致胸腺退化。该建议的中心假设是，在这些人群中，与年龄相关的p16Ink4a和Arf表达的增加是导致胸腺生成下降的关键事件。本提案的目的是检验这一假设，并产生"概念证明"数据，即靶向其表达，特别是通过使用激素和细胞因子，可以在治疗上用于恢复退化的胸腺。目标1中的初始实验将定义在衰老过程中何时以及在胸腺前和胸腺内发育的哪个阶段表达p16Ink4a和Arf，并确定它们的表达如何影响T细胞祖细胞的生长、分化和存活。目的2将确定p16Ink4a和Arf对胸腺退化的相对贡献，并确定下调其表达是否可以逆转该过程。在临床前研究和临床试验中，已经显示了诸如生长激素（GH）、胰岛素样生长因子-I（IGF-I）和角质细胞生长因子（KGF）的试剂使退化的胸腺恢复活力。然而，它们这样做的分子基础还不完全清楚。基于初步的数据，目标3将测试的假设，他们直接或间接介导的影响，通过下调p16Ink4a和Arf在未成熟的胸腺细胞的表达。总之，从这些研究中获得的数据将为胸腺退化提供分子基础，并对旨在逆转该过程的各种临床干预措施如何起作用提供机械理解。伴随胸腺退化的T细胞产生减少被认为是老年人细胞介导的免疫力下降的原因之一。如果能更好地理解这一过程，它可能会导致旨在恢复胸腺活力的疗法的发展。这反过来又意味着提高疫苗接种效率和恢复化疗或骨髓移植后的T细胞产生。

DESCRIPTION (provided by applicant): T cell precursors in the bone marrow and thymus undergo age-related declines in developmental potential that contribute to thymic involution. The central hypothesis of this proposal is that the age-related increase in expression of p16Ink4a and Arf in these populations is a key event that contributes to the decline in thymopoiesis. The goal of this proposal is to test this hypothesis and generate `proof of concept' data that targeting their expression, particularly through the use of hormones and cytokines, can be used therapeutically to rejuvenate the involuted thymus. Initial experiments in Aim 1 will define when and in which stages of pre-thymic and intra-thymic development p16Ink4a and Arf are expressed during aging and determine how their expression affects the growth, differentiation, and survival of T cell progenitors. Aim 2 will define the relative contribution of p16Ink4a and Arf to thymic involution and determine whether down-regulating their expression can reverse that process. Agents such as growth hormone (GH), Insulin Like Growth Factor-I (IGF-I), and Keratinocyte Growth Factor (KGF) have been shown in pre-clinical studies and clinical trials to rejuvenate the involuted thymus. However, the molecular basis by which they do so is incompletely understood. Based on preliminary data, Aim 3 will test the hypothesis that they mediate their effects directly or indirectly via down-regulation of p16Ink4a and Arf expression in immature thymocytes. Taken together, the data obtained from these studies will provide a molecular basis for thymic involution and a mechanistic understanding of how various clinical interventions designed to reverse that process are acting. A reduced T cell production that accompanies thymic involution is thought to be one reason for the decline in cell mediated immunity in the elderly. If this process could be better understood, it could lead to the development of therapies designed to rejuvenate the thymus. This in turn has implications for improving vaccination efficacy and restoration of T cell production following chemotherapy or bone marrow transplantation.