The role of Bcl-Rambo in thymic involution

说明(申请人提供)：胸腺退化是免疫系统随年龄增长而发生的主要变化之一(回顾(1))。胸腺的大小和功能的减少导致外周幼稚T细胞的数量减少，而外周记忆T细胞的平衡增殖弥补了这一点。因此，老年人T细胞抗原受体的多样性和免疫反应性降低。尽管在过去的几年中，衰老对胸腺细胞、胸腺前体细胞和胸腺微环境的影响已经得到了很好的描述，但导致胸腺退化的遗传决定因素和分子机制仍然知之甚少。我们最近发现，BclRambo是Bcl2家族中的一员，参与了胸腺退缩的调节。值得注意的是，缺乏这种蛋白质的小鼠的胸腺大小随着年龄的增长而变得更慢。这项拟议的项目旨在表征Bcl-Rambo在调节胸腺退化中的作用。这项研究可能导致确定药物干预的潜在靶点，以减轻胸腺退缩及其生理效应。BCL-Rambo是迄今为止最早被描述的蛋白质之一，它积极地调节与年龄相关的胸腺退化过程。通过这项应用，我们有机会评估与年龄相关的淋巴造血祖细胞功能缺陷的相对贡献；调节退缩的外周或胸腺内信号；以及胸腺微环境的变化，这些变化导致幼稚免疫细胞的产生、分化和功能下降。

DESCRIPTION (provided by applicant): Thymic involution is one the major changes that occur in the immune system with age (reviewed in (1)). The reduction of the size and function of the thymus lead to a decreased number of naive T cells in the periphery, compensated by homeostatic proliferation of peripheral memory T cells. As a consequence, the diversity of T cell antigen receptors and the immune responsiveness are reduced in aged individuals. Although the impact of aging on thymocytes, thymic progenitors and thymic microenvironment have been well characterized during the past few years, the genetic determinants and the molecular mechanisms responsible for thymic involution are still poorly understood. We recently discovered that Bcl-Rambo, a member of the Bcl-2 family of apoptotic regulators, is involved in the regulation of thymic involution. Notably, mice lacking this protein display a slower reduction of thymic size with age. The proposed project intends to characterize the role of Bcl-Rambo in the regulation of thymic involution. This study could lead to the identification of potential targets for pharmacological intervention to mitigate thymic involution and its physiological effects. Bcl-Rambo is one of the first proteins described to date, that positively regulates the process of age-related involution of the thymus. With this application we have the opportunity to assess the relative contributions of age-related deficiencies in lymphohematopoietic progenitor function; peripheral or intrathymic signals that regulate involution; and changes in the thymic microenvironment that contribute to the decline in na¿ve immune cell production, differentiation, and function.