INTERACTION OF MATRIX PROTEOGLYCANS WITH COMPLEMENT

基质蛋白聚糖与补体的相互作用

基本信息

批准号：
3085524
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
项目类别：
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/3085524
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

项目摘要

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.

补体系统是宿主防御的主要效应系统入侵微生物；然而，当过度激活或如果方向错误，它会对宿主组织造成损害。后者已被在自身免疫性疾病（例如胶原蛋白）的动物模型中得到证实诱发关节炎和膜性肾病，以及非免疫介导的原发性组织损伤，例如心肌缺血和热损伤。虽然已经取得了一些进展关于细胞表面补体活性的调节宿主组织的组成部分，关于细胞外如何成分调节补体介导的炎症。我们最近证明核心蛋白聚糖（一种硫酸皮肤素蛋白多糖）被广泛应用作为细胞外基质的组成部分分布，结合补体成分 C1q。结合是由核心蛋白聚糖核心蛋白介导的，相互作用导致浓度依赖性抑制补体激活的经典途径。另外，初步数据表明核心蛋白聚糖还通过以下方式抑制 C1q 介导的超氧化物产生中性粒细胞。该提案将检验核心蛋白聚糖和可能还有其他结构相关的蛋白多糖结合 C1q 并调节 C1q 介导的反应。具体来说，我们将通过以下方式检查该机制：其中核心蛋白聚糖抑制经典补体途径的活性，通过诱变将 C1q 结合位点定位在核心蛋白聚糖核心蛋白上人核心蛋白聚糖的cDNA，并通过以下方法确定其特异性和机制其中核心蛋白聚糖抑制中性粒细胞中 C1q 介导的超氧化物产生。最后，我们将检查另外两个结构是否相关蛋白聚糖、双糖链蛋白聚糖和 lumican 也结合 C1q 并干扰 C1 活动。