Effects of p16Ink4a and Arf on T Lineage Aging

描述（由申请人提供）：骨髓和胸腺中的T细胞前体经历与年龄相关的发育潜力下降，从而导致胸腺退化。该建议的中心假设是p16Ink4a和Arf在这些人群中与年龄相关的表达增加是导致胸腺功能下降的关键事件。这项提议的目标是测试这一假设，并产生“概念证明”数据，以它们的表达为目标，特别是通过使用激素和细胞因子，可以用于治疗性地恢复胸腺的活力。Aim 1的初始实验将确定p16Ink4a和Arf在胸腺前和胸腺内发育的何时和哪个阶段在衰老过程中表达，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，并确定下调它们的表达是否可以逆转这一过程。生长激素（GH）、胰岛素样生长因子- i （IGF-I）和角化细胞生长因子（KGF）等药物已在临床前研究和临床试验中被证明可以使受累胸腺恢复活力。然而，它们这样做的分子基础还不完全清楚。基于初步数据，Aim 3将验证它们通过下调未成熟胸腺细胞中p16Ink4a和Arf表达直接或间接介导其作用的假设。综上所述，从这些研究中获得的数据将为胸腺退化提供分子基础，并对旨在逆转这一过程的各种临床干预措施如何起作用提供机制理解。伴随胸腺退化的T细胞生成减少被认为是老年人细胞介导免疫力下降的原因之一。如果这一过程能被更好地理解，它可能会导致旨在使胸腺恢复活力的疗法的发展。这反过来又对提高疫苗接种效果和化疗或骨髓移植后T细胞生产的恢复具有意义。

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.