The role of Bcl-Rambo in thymic involution

描述（由申请人提供）：胸腺退化是随着年龄增长而发生的免疫系统主要变化之一（见(1)）。胸腺大小和功能的减少导致外周幼稚T细胞数量的减少，外周记忆T细胞的稳态增殖补偿。因此，老年人的T细胞抗原受体多样性和免疫反应性降低。尽管在过去的几年里，衰老对胸腺细胞、胸腺祖细胞和胸腺微环境的影响已经得到了很好的表征，但对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Bcl-Rambo是凋亡调节因子Bcl-2家族的一员，参与胸腺退化的调节。值得注意的是，缺乏这种蛋白质的小鼠随着年龄的增长胸腺大小的缩小速度较慢。拟议的项目旨在表征Bcl-Rambo在胸腺退化调节中的作用。这项研究可能有助于确定药物干预的潜在靶点，以减轻胸腺退化及其生理影响。Bcl-Rambo是迄今为止第一批被描述的蛋白质之一，它积极调节与年龄相关的胸腺退化过程。通过这一应用，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；调节复归的外周或胸腺内信号；胸腺微环境的改变会导致免疫细胞的产生、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.