APOPTOSIS IN RHEUMATOID ARTHRITIS

描述：(改编自申请人的摘要)-这是一份 应用于检验关于类风湿性关节炎发病机制的新假说；即， P53突变在滑膜增生性扩张中起作用 炎症的后果。活性氧(ROS)和细胞因子， 存在于RA关节中，是活性的凋亡诱导剂，它应该 通常会抵消组织的扩张。申请者提出，基因突变 P53可能是长期暴露在诱变作用下的结果 ROS和细胞因子，而且这种突变会产生一种状态 ROS和/或细胞因子诱导的细胞DNA损伤对细胞凋亡的抵抗作用 滑膜细胞。这种对凋亡的抵抗会导致细胞堆积 尽管有轻微的增殖和这种扩张导致血管疙瘩和关节 损坏。因此，虽然类风湿关节炎可能主要是一种免疫性疾病， 特别是在最初，申请人认为非免疫性 事件(如P53介导的细胞凋亡反应中的体细胞缺陷)使 对疾病的发展有重大贡献。他们计划检查 P53在ROS及相关细胞因子诱导的细胞凋亡中的作用 细胞类型(巨噬细胞、成纤维细胞样滑膜细胞)及相关细胞。 这将在培养中通过使用对温度敏感的p53来完成。 允许有条件的p53在多种细胞中发挥作用的突变体。自.以来 P53在许多细胞中是必需的，以诱导DNA后的细胞凋亡 损害代理人，申请人预计它将在这里发挥这样的作用 井。同时，申请者将检查RA关节组织以检查 存在P53突变。然后他们将确定P53的影响 滑膜细胞功能的突变。最后，他们将评估P53的作用 在缺乏该基因的小鼠的细胞凋亡和疾病进展中 靶向破坏，在这种情况下，它们将通过以下方式引发关节炎症 免疫学手段。总而言之，这些研究将构成严格的 追求这种模式，如果成功，他们相信 研究将对我们理解RA和 提供新的治疗策略。

DESCRIPTION: (Adapted from the applicant's abstract) - This is an application to test a novel hypotheses on the pathogenesis of RA; namely, that p53 mutations play a role in hyperplastic expansion of the synovium as a consequence of inflammation. Reactive oxygen species (ROS) and cytokines, present in the RA joint, are active apoptosis inducers, which should normally offset tissue expansion. The applicants propose that mutations in p53 can occur as a consequence of long-term exposure to the mutagenic action of ROS and cytokines, and further, that such mutations produce a state of resistance to apoptosis caused by ROS- and/or cytokine-induced DNA damage of synoviocytes. This resistance to apoptosis causes an accumulation of cells despite modest proliferation and this expansion results in pannus and joint damage. Thus, while RA may be predominantly an immunological disease, particularly at its inception, the applicants believe that nonimmunologic events (such as somatic defects in p53-mediated apoptotic response) make a major contribution to the progression of the disease. They plan to examine the role of p53 in apoptosis induced by ROS and cytokines in the relevant cell types (macrophages, fibroblasts-like synovial cells) and related cells. This will be done in culture, through the use of temperature-sensitive p53 mutants that permit conditional p53 function in a variety of cells. Since p53 is required in many cells for the induction of apoptosis following DNA damaging agents, the applicants expect that it will have such a role here as well. Concurrently, the applicants will examine RA joint tissues for the presence of p53 mutations. Then they will determine the influences of p53 mutation on synoviocyte function. Finally, they will assess the role of p53 in apoptosis and disease progression in mice lacking this gene through targeted disruption, in which they will induce joint inflammation by immunologic means. Together, these studies will form the basis for rigorous pursuit of this model, and if successful, it is their belief that the studies will have important consequences for our understanding of RA and provide new therapeutic strategies.