SIGNAL PATHWAY--INTERSTIT COLLAGE TRANSCRIPT

间质胶原酶是滑膜成纤维细胞产生的一种酶。 这对类风湿性关节炎的病理生理学有贡献。在这 疾病，滑膜成纤维细胞被炎症信号激活，如 作为白介素1(IL-1)，并产生不适当的高水平 Callagenase，促进软骨、韧带和 骨头。尽管胶原酶基因激活在类风湿关节炎中的重要性，但 导致胶原酶转译增加的信号通路还没有 已经被定义了。我最近进行的研究表明，在 V-src对IL-1的作用是胶原酶的有效激活剂 抄写。此外，IL-1和v-src可以协同作用 激活胶原酶启动子，提示这些刺激物 共同的信号中间产物。开始定义路径(S) 导致胶原酶转录，转录因子激活b V-src与近端胶原酶启动子相互作用 特色化的。V-src的下游调节因子，如映射激酶，将 这些下游激酶的功能将被识别出来 在表达v-src的滑膜成纤维细胞中检测。两者之间的协同效应 V-src和IL-1可能是由于src相关的激酶，它是一种 IL-1依赖途径的中间体。要探索这一点 有可能，显性负性v-src将作为一种特定的抑制剂进行测试。 IL-1诱导的胶原酶转录。或者，转录 由v-src和IL-1激活的因子可能在物理上相互作用 细胞核协同招募RNA聚合酶II到 胶原酶启动子。因此，潜在的蛋白质-蛋白质相互作用 将测试v-src和IL-1诱导的转录因子之间的关系 通过使用酵母双杂交系统。这一方法也将是 用于识别信号转导蛋白，如映射激酶，它 与激活这些转录因子相互作用。这项工作将为 第一次，描述了特定的蛋白激酶和转录因子 它们相互作用于胶原酶所涉及的信号通路 转录将导致对分子的更好的理解 结缔组织病的发病机制。

Interstitial collagenase is an enzyme produced by synovial fibroblasts which contributes to the pathophysiology of rheumatoid arthritis. In this disease, synovial fibroblasts are activated by inflammatory signals, such as interleukin-1 (IL-1 and produce inappropriately high levels of callagenase, contributing to the degradation of cartilage, ligament and bone. Despite the importance of collagenase gene activation in RA, the signaling pathways leading to increased collagenase transcrption have not been defined. Recent studies I have conducted demonstrate that in addition to IL-1 by v-src is a potent activator of collagenase transcription. Furthermore, IL-1 and v-src can work synergistically to activate the collagenase promoter, suggesting these stimuli share common signaling intermediates. To begin to define the pathway (s) leading to collagenase transcription, the transcription factors activated b v-src and interact with the proximal collagenase promoter will be characterized. Downstream mediators of v-src, such as Map kinases will be identified and the function of these downstream kinases will be assayed in synovial fibroblasts expressing v-src. The synergism between v-src and IL-1 may be due to a src-related kinase which is an intermediate in the the IL-1 dependent pathway. To explore this possibility, a dominant negative v-src willbe tested as a specific inhibito of IL-1 induced collagenase transcription. Alternatively, transcription factors which are activated by v-src and IL-1 may physically interact in the nucleus to cooperatively recruit RNA polymerase II to the collagenase promoter. Thus, potential protein-protein interactions between v-src and IL-1 induced transcription factors will be tested through use of the yeast two hybrid system. This approach will also be used to identify signal transducing proteins, such as Map kinases which interact with activate these transcription factors. This work will, for th first time, descrive the specific protein kinases and transcription factor which interact the signaling pathways involved in collagenase transcription will lead to a better understanding of the molecular mechanisms of connective tissue disease.