INTERACTION OF MATRIX PROTEOGLYCANS WITH COMPLEMENT

基质蛋白聚糖与补体的相互作用

• 批准号: 2057305
• 负责人: RICHARD KRUMDIECK
• 金额: $ 7.88万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2057305
• 关键词: chemical binding; complement; complement pathway; extracellular matrix; gene deletion mutation; inflammation; leukocyte oxidative burst; molecular cloning; neutrophil; protein purification; proteoglycan; superoxides; tissue /cell culture; transfection; chemical binding; complement; complement pathway; extracellular matrix; gene deletion mutation; inflammation; leukocyte oxidative burst; molecular cloning; neutrophil; protein purification; proteoglycan; superoxides; tissue /cell culture; transfection

The complement system is a major effector system of host defense against invading microorganisms; however, when excessively activated or misdirected, it can produce damage to host tissues. The latter has been demonstrated in animal models of autoimmune diseases such as collagen- induced arthritis and membranous nephropathy, as well as in non- immunologically mediated forms of primary tissue damage such as myocardial ischemia and thermal injury. While several advances have been made concerning the regulation of complement activity by cell-surface Components of host tissues, little is known about how extracellular components regulate complement-mediated inflammation. We recently demonstrated that decorin, a dermatan-sulfate proteoglycan widely distributed as a component of extracellular matrices, binds complement component C1q. Binding is mediated by the decorin core protein, and the interaction results in a concentration-dependent inhibition of the classical pathway of complement activation. In addition, preliminary data shows that decorin also inhibits C1q-mediated superoxide production by neutrophils. This proposal will test the hypothesis that decorin and possibly other structurally related proteoglycans bind C1q and regulate C1q-mediated reactions. Specifically, we will examine the mechanism by which decorin inhibits the activity of the classical complement pathway, map the C1q binding site on the decorin core protein by mutagenesis of the cDNA of human decorin, and determine the specificity and mechanism by which decorin inhibits C1q-mediated superoxide production in neutrophils. Lastly, we will examine whether two other structurally related proteoglycans, biglycan and lumican, also bind C1q and interfere with C1 activity.

补体系统是主机防御的主要效应器系统 入侵微生物；但是，当过度激活或 被误导，它会对宿主组织造成损害。 后者已经 在自身免疫性疾病的动物模型中证明了 诱导关节炎和膜性肾病，以及非 - 免疫学介导的原发性组织损伤，例如心肌损伤 缺血和热损伤。虽然已经取得了一些进步 关于通过细胞表面调节补体活动的调节 宿主组织的组成部分，对细胞外几乎一无所知 组件调节补体介导的炎症。 我们最近 证明了Decorin，Dermatan-sulfate蛋白聚糖广泛 分布成细胞外矩阵的组成部分，结合补体 组件C1Q。 绑定是由Decorin核心蛋白介导的， 相互作用导致浓度依赖性抑制 补体激活的经典途径。 此外，初步数据 表明Decorin还通过抑制C1Q介导的超氧化物产生 中性粒细胞。 该提议将检验以下假设： 可能其他与结构相关的蛋白聚糖结合C1q并调节 C1Q介导的反应。 具体来说，我们将通过 Decorin抑制了经典补体途径的活性， 绘制Decorin核心蛋白上的C1Q结合位点的诱变 人类装饰的cDNA，并通过 装饰蛋白抑制了中性粒细胞中C1Q介导的超氧化物的产生。 最后，我们将研究其他两个与结构相关的 蛋白聚糖，大型群和Lumican也结合C1q并干扰C1 活动。