COLLAGEN SYNTHESIS IN INFLAMMATION

退行性和炎症性关节疾病的特点是 关节细胞外基质重塑的研究进展 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，以及这一研究的总体目标 建议是定义潜在的细胞和分子机制 伴随着缺陷修复的胶原合成的改变 关节炎的过程。在这项提案中，我们将继续研究 都专注于调节组织特异性模式的细胞因子 结缔组织细胞表达的胶原蛋白类型。我们有 建立正常人和/或永生化人的细胞培养模型 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。这些研究集中在类型的表达上 I型胶原基因。我们已经开始刻画类型的表达方式 这些细胞对白介素1(IL-1)、肿瘤细胞的I型胶原反应 肿瘤坏死因子-α(TNF-α)和干扰素-γ(IFN-γ)， 细胞因子与病理性结缔组织重塑 与炎症性疾病相关，并定义反馈 前列腺素(PGE2)的调节作用。这些细胞因子的结合和 前列腺素对特定细胞表面受体的作用 每种类型可能由不同的信号事件和 诱导或调节细胞特异性转录因子。这个 具体目标是：(1)进一步塑造和发展不朽 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-1的差异性反应 α、干扰素-γ和前列腺素E_2。(3)确定是否已知抄写 参与调节胶原基因表达的因子 IL-1、肿瘤坏死因子-α、干扰素-γ和前列腺素E_2的相互作用 细胞因子反应性和组织特异性调节因子。(4)识别唯一 决定这些模型中细胞特异性细胞因子反应的基因(S) 通过差异克隆技术，鉴定和鉴定 新基因产品(S)。拟议的研究将提供新的信息 关于细胞因子和前列腺素如何阻止适当的修复 风湿病中的关节组织。这种方法可以允许 靶向特定信号通路及其相关转录 因子与药理作用，以解益气 细胞因子和前列腺素的毒副作用 关于关节炎症和退化的研究。

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.