COLLAGEN SYNTHESIS IN INFLAMMATION

退行性和炎性关节疾病的特征在于： 关节细胞外基质重塑紊乱 组织，包括软骨、骨和滑膜。 胶原蛋白是一种主要的 这些结缔组织的组成部分，这一总体目标， 建议是确定细胞和分子机制， 胶原蛋白合成的改变伴随着修复缺陷 关节炎的过程。 在这项建议中，我们将继续研究， 一直专注于调节组织特异性模式的细胞因子， 结缔组织细胞表达胶原类型。 我们有 建立正常和/或永生化人的人细胞培养模型 滑膜和真皮成纤维细胞、关节和肋软骨细胞，以及 成骨细胞样细胞。 这些研究集中在表达的类型 I胶原基因。 我们已经开始描述 I型胶原通过这些细胞对白细胞介素-1（IL-1）、肿瘤 坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）， 病理性结缔组织重塑中的细胞因子 与炎症性疾病相关，并定义反馈 前列腺素（PGE 2）的调节作用。 这些细胞因子的结合， 对特异性细胞表面受体的三尖杉酯碱诱导的反应， 每种类型可能由不同的信号事件介导， 诱导或调节细胞特异性转录因子。 的 具体目的是：（1）进一步表征和开发永生化 人细胞系作为研究细胞特异性反应的模型 细胞因子 (2)确定潜在的分子机制 人结缔组织细胞对IL-1，TNF-α， α干扰素γ和前列腺素E2 (3)确定是否已知转录 因子参与调节胶原蛋白基因的表达， 与IL-1、TNF-α、IFN-γ和PGE 2的相互作用， 尼古丁反应性和组织特异性调节剂。 (4)确定独特的 在这些模型中决定细胞特异性细胞因子应答的基因 通过差异克隆技术， 新的基因产物。 拟议的研究将提供新的信息 关于细胞因子和肾上腺素如何阻止 风湿性疾病的关节组织。 这种方法可以使 靶向特定的信号通路和相关的转录 与药理学试剂的因素，以分离有益的 细胞因子和野牡丹素的作用与它们的有害作用 对关节炎症和退化的影响

Degenerative and inflammatory joint diseases are characterized by disturbances in the remodeling of the extracellular matrix of joint tissues, including cartilage, bone, and synovium. Collagen is a major constituent of these connective tissues, and the overall goal of this proposal is to define the cellular and molecular mechanisms underlying the altered collagen synthesis that accompanies the defective repair processes in arthritis. In this proposal we will continue studies that have focused on cytokines that regulate the tissue-specific patterns of expression of collagen types by connective tissue cells. We have established human cell culture models of normal and/or immortalized human synovial and dermal fibroblasts, articular and costal chondrocytes, and osteoblast-like cells. These studies focus on the expression of the type I collagen gene. We have begun to characterize the expression of type I collagen by these cells in response to interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma), cytokines implicated in the pathological connective tissue remodeling associated with inflammatory disorders, and to define the feedback modulatory role of prostaglandin (PGE2). Binding of these cytokines and prostaglandins to specific cell-surface receptors induces responses in each type that are probably mediated by distinct signaling events and induction or modulation cell-specific transcription factors. The Specific Aims are: (1) Further characterize and develop immortalized human cell lines as models for studying cell-specific responses to cytokines. (2) Determine the molecular mechanisms underlying the differential responses of human connective tissue cells of IL-1, TNF- alpha, IFN-gamma, and PGE2. (3) Determine whether known transcription factor are involved in regulating collagen gene expression in response to IL-1, TNF-alpha, IFN-gamma and PGE2 and define interactions among cytokine-responsive and tissue-specific regulators. (4) Identify unique gene(s) that determine cell-specific cytokine responses in these models by differential cloning techniques and identify and characterize the novel gene product(s). The proposed studies will provide new information about how cytokines and prostaglandins prevent appropriate repair of joint tissues in rheumatic diseases. This approach could permit targeting of specific signaling pathways and associated transcription factors with pharmacological agents in order to dissociate the beneficial effects of cytokines and prostaglandins from their detrimental effects on joint inflammation and degradation.