The role of Bcl-Rambo in thymic involution

Bcl-Rambo 在胸腺复旧中的作用

• 批准号: 8013807
• 负责人: Richard A. Flavell
• 金额: $ 40.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-17 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013807
• 关键词: Age; Aging; Aging-Related Process; Apoptotic; Cell physiology; Cells; Development; Family; Genetic Determinism; Immune; Immune system; Individual; Intervention; Lead; Lymphoid; Molecular; Mus; Peripheral; Physiological; Production; Proteins; Regulation; Relative (related person); Role; Signal Transduction; T memory cell; T-Cell Receptor; T-Lymphocyte; Thymocyte Development; Thymus Gland; age related; aged; member; progenitor; thymocyte

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.

描述（由适用提供）：胸腺涉及是随着年龄的增长（在（1）中审查）中发生在免疫系统中的主要变化之一。胸腺的大小和功能的降低导致外周中的幼稚T细胞数量减少，并通过外围记忆T细胞的稳态增殖而补偿。结果，老年个体中T细胞抗原受体的多样性和免疫回避性降低。尽管衰老对胸腺细胞，胸腺祖细胞和胸腺微环境的影响在过去几年中已经很好地表征了，但遗传决定剂和负责胸腺涉及的分子机制仍然知之甚少。我们最近发现，BCL-2的凋亡调节剂家族的成员BCL-Rambo参与了胸腺冲突的调节。值得注意的是，缺乏该蛋白质的小鼠随着年龄的增长而显示出胸膜大小的降低。拟议的项目旨在表征BCL-Rambo在调节胸腺相互作用中的作用。这项研究可能导致鉴定出药物干预的潜在靶标，以减轻胸腺疾病及其物理作用。 BCL-Rambo是迄今为止描述的第一批蛋白质之一，它对胸腺与年龄相关的相关性过程进行了积极调节。通过此应用，我们有机会评估淋巴结质祖细胞功能中与年龄相关的缺陷的相对贡献；调节相关性的外周或胸膜信号；以及胸腺微环境的变化，导致NA¿VE免疫物产生，分化和功能的下降。