RHEUMATOID ARTHRITIS, PHOSPHOLIPASES AND INFLAMMATION

描述：(改编自申请者的摘要)炎症 许多设置似乎由和/或放大了 磷脂酶。这位调查员和他的同事们表现出了 兔关节滑膜细胞和滑液中磷脂酶A2酶活性的研究 类风湿性关节炎患者。他们还发现， 鉴定了一种磷脂酶A2激活蛋白(PLAP)，并具有 证明了这种蛋白质对细胞和磷脂酶的影响 A2.他们已经证明，将PLAP注射到兔关节中已经 导致炎症性关节炎反应，这与 类风湿关节炎。此外，外周血液暴露 白细胞的PLAP导致了二十烷类化合物和超氧化物的产生 伴随着细胞脱颗粒而产生。他们最近克隆了 获得了PLAP的全长c DNA。他们还产生了初步的 磷脂酶A2激活作用机制的证据 代表了细胞内钙离子增加的替代方案 集中精神。 在本项目的第四次提交中，先前于12月进行了评判 1993年曾是本委员会的杰出人物， 研究人员建议继续这些研究。在第一个下 有针对性的，它们将在体外表达PLAP，大量纯化PLAP， 对纯化的蛋白质进行鉴定，获得氨基酸序列。 在第二个具体目标下，调查人员将克隆PLAP 一个人的cdna来源。他们将评估PLAP的遗传调控。 由炎性刺激产生，并作为这一新的组成部分 具体目的，他们将描述动物体内PLAP的活性 PLAP诱导的类风湿性关节炎模型。

DESCRIPTION: (Adapted from the applicant's abstract) Inflammation in many settings appears to be mediated by and/or amplified by phospholipase. This investigator and his colleagues have shown enhanced phospholipase A2 enzyme activities in cells and synovial fluid from patients with rheumatoid arthritis. They have also discovered and characterized a phospholipase A2 activating protein (PLAP) and have demonstrated the consequences of this protein on cells and phospholipase A2. They have shown that injection of PLAP into rabbit joints has resulted in an inflammatory arthritis response which closely resembles rheumatoid arthritis. In addition, exposure of peripheral blood leukocytes to PLAP has resulted in an eicosanoid and superoxide generation along with cellular degranulation. They have recently cloned and obtained the cDNA for PLAP. They also have generated preliminary evidence for a mechanism of action for phospholipase A2 activation that represents an alternative to an increase in intracellular calcium concentration. In this fourth submission of this project, previously judged in December 1993 to have been on the cusp of outstanding by this committee, the investigator proposes to continue these studies. Under the first specific aim, they will express PLAP in vitro, purify PLAP in quantity, characterize the purified protein, and obtain amino acid sequences. Under the second specific aim, the investigators will clone PLAP from a human cDNA source. They will evaluate the genetic regulation of PLAP production by inflammatory stimuli and as a new component of this specific aim, they will characterize the activity of PLAP in an animal model of PLAP-induced rheumatoid arthritis.