SPECIFIC INHIBITORS OF GLOMERULONEPHRITIS

转化生长因子-β 在发病机制中发挥核心作用 多种纤维化疾病，包括肾小球肾炎、糖尿病 肾炎、肝硬化、肺纤维化。 人核心蛋白聚糖是 结合并中和 TGF-β 作用的蛋白多糖 防止实验动物纤维化。 除了TGF-β 结合，核心蛋白聚糖表现出胶原结合和受体介导 被培养细胞内化，导致其新陈代谢。 的 核心蛋白聚糖的作用机制似乎不仅仅涉及 TGF-β 结合 因为结合 TGF-β 的肽和片段中的修饰不会出现 以起到中和作用。 该提案将使用肽和 核心蛋白聚糖重组片段探索胶原蛋白结合的作用 TGF-β 机制中的受体介导的内化 中和。 核心蛋白聚糖作为治疗药物的临床前开发 将启动肾小球肾炎，包括检测开发和 验证以支持稳定性研究，然后进行毒理学研究 通过连续输注给大鼠和灵长类动物施用核心蛋白聚糖。 这些 研究将使我们了解核心蛋白聚糖的作用机制和 提供申请研究性新药所需的数据 申请启动核心蛋白聚糖在人类疾病中的临床测试。

Transforming growth factor-beta plays a central role in the pathogenesis of a variety of fibrotic diseases including glomerulonephritis, diabetic nephritis, liver cirrhosis, and pulmonary fibrosis. Human decorin is a proteoglycan that binds and neutralizes the action of TGF-beta and prevents fibrosis in experimental animals. In addition to TGF-beta binding, decorin exhibits collagen binding and receptor-mediated internalization by cultured cells, leading to its metabolism. The mechanism of decorin action appears to involve more than TGF-beta binding because decor in peptides and fragments that bind TGF-beta do not appear to have a neutralizing effect. This proposal will use peptides and recombinant fragments of decorin to explore the role of collagen binding and receptor-mediated internalization in the mechanism of TGF-beta neutralization. Pre-clinical development of decorin as a treatment for glomerulonephritis will be initiated, including assay development and validation to support stability studies, followed by toxicology studies of decorin administered by continuous infusion into rats and primates. These studies will allow us to understand the mechanism of decorin action and provide the necessary data for filing an Investigational New Drug application to initiate clinical testing of decorin in human disease.