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Effects of p16Ink4a and Arf on T Lineage Aging

p16Ink4a 和 Arf 对 T 谱系衰老的影响

基本信息

批准号：
8422981
负责人：
KENNETH Allan DORSHKIND
金额：
$ 34.2万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-15 至 2014-02-28
项目状态：
已结题

项目摘要

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.

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。该提议的中心假设是，这些人群中 p16Ink4a 和 Arf 表达与年龄相关的增加是导致胸腺生成功能下降的关键事件。该提案的目的是检验这一假设并生成针对其表达的“概念验证”数据，特别是通过使用激素和细胞因子，可以在治疗上用于使退化的胸腺恢复活力。目标 1 中的初步实验将确定 p16Ink4a 和 Arf 在衰老过程中在胸腺前和胸腺内发育的时间和哪个阶段表达，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。目标 2 将定义 p16Ink4a 和 Arf 对胸腺复旧的相对贡献，并确定下调它们的表达是否可以逆转该过程。临床前研究和临床试验表明，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) 等药物可以使退化的胸腺恢复活力。然而，它们这样做的分子基础尚不完全清楚。根据初步数据，Aim 3 将测试以下假设：它们通过下调未成熟胸腺细胞中的 p16Ink4a 和 Arf 表达直接或间接介导其作用。总而言之，从这些研究中获得的数据将为胸腺复旧提供分子基础，并从机制上理解旨在逆转这一过程的各种临床干预措施如何发挥作用。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的免疫力下降的原因之一。如果能够更好地理解这一过程，可能会导致开发出旨在使胸腺恢复活力的疗法。这反过来又对提高疫苗接种效果和恢复化疗或骨髓移植后 T 细胞的产生具有影响。