A NOVEL T CELL ACTIVATION CONTROLLED BY A DISEASE GENE

由疾病基因控制的新型 T 细胞激活

• 批准号: 6626996
• 负责人: DONALD BELLGRAU
• 金额: $ 32.28万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6626996
• 关键词: T cell receptor; T lymphocyte; antigen receptors; autoantigens; cyclin dependent kinase; cytokine receptors; diabetes mellitus genetics; disease /disorder model; enzyme inhibitors; genetic susceptibility; immunogenetics; insulin dependent diabetes mellitus; interleukin 2; laboratory rat; leukocyte activation /transformation; lymphopenia; mitogen activated protein kinase; proliferating cell nuclear antigen; retinoblastoma protein

DESCRIPTION: (Adapted from the Investigator's abstract): The development of diabetes spontaneously in the BB rat requires a diabetogenic gene termed lyp. Lyp is named after the phenotype it creates, peripheral T cell lymphopenia. Most T cells from lymphopenic animals have a dramatically shortened life span and when they fail to become members of the long lived peripheral T cell pool the lymphopenic environment is created. A major focus of our work has been directed to understanding how the lyp gene and the resultant lymphopenia contribute to disease. Our recent observations indicate that most T cells from diabetes-prone BB animals express a novel activation state, defined by a quiescent cell surface but activated internal measures of cell cycle machinery. We believe this novel activation state is the impetus through which autoreactive T cells become activated. In this application we will test several hypotheses formulated from our data. First, the cause of the lymphopenia is the lyp gene mediated cell cycle arrest of T cells as they attempt to progress from G1 to S phase. Second, lymphopenia creates space in the periphery. Space provides clonal expansion signals for recent thymic emigrants that bear T cell receptors for self antigens. Third, autoreactive T cells can overcome the lyp gene mediated cell cycle arrest because they express high affinity receptors for self antigens. If our hypotheses are correct, as tested in the experiments proposed in this application, the data generated will permit us to understand how at least one genetic susceptibility region contributes to disease in this rat model.

描述：（改编自研究者的摘要）： BB 大鼠自发性糖尿病需要一种称为 lyp 的糖尿病基因。 Lyp 以其产生的表型命名，即外周 T 细胞淋巴细胞减少症。 大多数来自淋巴细胞减少动物的 T 细胞的寿命显着缩短 当它们未能成为长寿外周 T 细胞库的成员时 创建淋巴细胞减少环境。我们工作的一个主要重点是 旨在了解 lyp 基因和由此产生的淋巴细胞减少症如何 促成疾病。我们最近的观察表明，大多数 T 细胞来自 易患糖尿病的 BB 动物表现出一种新的激活状态，其定义为 静止的细胞表面，但激活细胞周期机制的内部措施。 我们相信这种新颖的激活状态是推动 自身反应性 T 细胞被激活。在此应用程序中，我们将测试几个 根据我们的数据提出的假设。首先，淋巴细胞减少的原因是 lyp 基因介导 T 细胞的细胞周期停滞，因为它们试图从 G1期至S期。其次，淋巴细胞减少在周围产生空间。空间 为最近携带 T 细胞的胸腺移出物提供克隆扩增信号 自身抗原的受体。第三，自身反应性T细胞可以克服lyp 基因介导的细胞周期停滞，因为它们表达高亲和力受体 对于自身抗原。如果我们的假设是正确的，正如实验所检验的那样 在此应用程序中提出，生成的数据将使我们能够理解 至少一个遗传易感区域如何导致这一疾病 大鼠模型。