HGF Gene Therapy for Chronic Renal Fibrosis

描述(申请人提供)：终末期肾病(ESRD)是 最具破坏性的疾病，发病率和死亡率都很高， 全世界的患者数量都在上升。尽管初选多种多样 病因，慢性肾脏疾病进展为终末期肾病的发病机制是 非常单调的过程，其特征是无情地积累 细胞外基质(ECM)导致广泛的组织纤维化。因此， 开发一种抑制纤维化的方案似乎是 慢性肾脏疾病的治疗。我们实验室的初步研究 提示肝细胞生长因子(HGF)是一种重要的调节因子。 细胞外基质转化抑制组织纤维化的研究 肾脏疾病的动物模型。因为外源性HGF在血液中非常不稳定 循环由于肝脏的快速清除，我们最近开发了一种基因 利用裸质粒载体高效表达的转移策略 体内的肝细胞生长因子蛋白。根据这些结果，我们假设 肝细胞生长因子基因是治疗慢性粒细胞白血病的有效策略 肾脏疾病。在这个应用中，我们建议将HGF基因导入到 建立进展性肾病动物模型，评价其治疗效果。 我们将通过以下方式探讨HGF改善肾纤维化的机制 检测肌成纤维细胞激活和转化生长因子-β1信号转导的调节。 这些将在以下三个具体目标中实现：1)评估 肝细胞生长因子基因治疗慢性肾纤维化的疗效观察 肝细胞生长因子在肾脏肌成纤维细胞活化中的作用 肝细胞生长因子阻断促纤维化细胞因子转化生长因子-β1的分子机制 发信号。这些研究将提供基本信息，如 肝细胞生长因子基因治疗慢性肾脏疾病的可行性和有效性 将最终导致人类慢性肾脏的新治疗策略 纤维化，否则是无法治愈的。

DESCRIPTION (Provided by applicant): End-stage renal disease (ESRD) is one of the most devastating diseases with great morbidity and mortality, and the number of patients is on the rise worldwide. Despite diverse primary etiologies, the pathogenesis of chronic renal diseases progressing to ESRD is a remarkably monotonous process characterized by relentless accumulation of extracellular matrix (ECM) leading to widespread tissue fibrosis. Thus, developing a scheme to inhibit fibrosis appears to be a key strategy for the treatment of chronic renal disease. Preliminary studies in our laboratory suggest that hepatocyte growth factor (HGF) is an important regulator of extracellular matrix turnover leading to inhibition of tissue fibrosis in animal model of renal diseases. Because exogenous HGF is very unstable in blood circulation due to the rapid clearance by liver, we recently develop a gene transfer strategy using naked plasmid vector resulting in efficient expression of HGF protein in vivo. Based on these results, we hypothesize that delivery of HGF gene is an effective therapeutic strategy for the treatment of chronic renal disease. In this application, we propose to administrate HGF gene into animal model of progressive renal disease to evaluate its therapeutic efficacy. We will investigate the mechanism underlying HGF ameliorating renal fibrosis by examining the regulation of myofibroblast activation and TGF-Beta1 signaling. These will be accomplished in the following three specific aims: 1) to evaluate the efficacy of HGF gene therapy for chronic renal fibrosis; 2) to investigate the role of HGF in renal myofibroblast activation; 3) to elucidate the molecular mechanism underlying HGF blocking pro-fibrogenic cytokine TGF-Beta1 signaling. These studies will provide fundamental information such as the feasibility and efficacy of HGF gene therapy for chronic renal diseases, and will eventually lead to new therapeutic strategies to human chronic renal fibrosis, which is otherwise incurable.