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，这有助于胸腺退化。这一建议的中心假设是，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。这项提议的目的是检验这一假设，并产生“概念证明”数据，即针对它们的表达，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的活力。目标1的初步实验将确定胸腺前和胸腺内发育的p16INK4a和Arf在衰老过程中何时和在哪个阶段表达，并确定它们的表达如何影响T细胞前体细胞的生长、分化和存活。目标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)和角质形成细胞生长因子(KGF)等药物已在临床前研究和临床试验中被证明可以使退缩的胸腺恢复活力。然而，他们这样做的分子基础还没有完全被理解。基于初步数据，AIM 3将检验这一假设，即它们直接或间接地通过下调未成熟胸腺细胞中p16INK4a和Arf的表达来调节其效果。总而言之，从这些研究中获得的数据将为胸腺退化提供分子基础，并从机制上理解旨在逆转这一过程的各种临床干预措施是如何起作用的。伴随着胸腺退化而产生的T细胞减少被认为是老年人细胞免疫功能下降的原因之一。如果能更好地了解这一过程，它可能会导致旨在恢复胸腺活力的疗法的开发。这反过来又对提高疫苗接种效率和恢复化疗或骨髓移植后T细胞的产生产生了影响。

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.