SPECIFIC INHIBITORS OF GLOMERULONEPHRITIS

转化生长因子-β在发病机制中起着重要作用 各种纤维化疾病，包括肾小球肾炎，糖尿病 肾炎、肝硬化和肺纤维化。 人类核心蛋白聚糖是一种 结合并中和TGF-β作用的蛋白聚糖， 防止实验动物的纤维化。 除了TGF-β 结合，核心蛋白聚糖表现出胶原结合和受体介导的 通过培养的细胞内化，导致其代谢。 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decor并没有出现， 有中和作用。 该提案将使用肽和 核心蛋白聚糖的重组片段，以探索胶原结合的作用 和受体介导的内化在TGF-β的机制 中和 核心蛋白聚糖作为治疗的临床前开发 将启动肾小球肾炎试验，包括试验开发和 验证以支持稳定性研究，然后进行毒理学研究 核心蛋白聚糖通过连续输注给大鼠和灵长类动物。 这些 研究将使我们了解核心蛋白聚糖的作用机制， 提供申报新药研究所需的数据 申请启动核心蛋白聚糖在人类疾病中的临床试验。

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.