HGF Gene Therapy for Chronic Renal Fibrosis

HGF基因治疗慢性肾纤维化

• 批准号: 6460373
• 负责人: YOUHUA LIU
• 金额: $ 22.45万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6460373
• 关键词: biological signal transduction; cell proliferation; chronic renal failure; disease /disorder model; disease /disorder prevention /control; enzyme linked immunosorbent assay; extracellular matrix; fibroblasts; fibrogenesis; fibrosis; gene delivery system; gene therapy; genetically modified animals; hepatocyte growth factor; immunocytochemistry; laboratory mouse; nonhuman therapy evaluation; pathologic process; phosphorylation; receptor expression; terminal nick end labeling; tissue /cell culture; transfection /expression vector; transforming growth factors; western blottings

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.

描述（由申请人提供）：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， 全球患者数量正在上升。尽管初级 慢性肾病进展为终末期肾病的发病机制是一种 一个以不断积累为特征的非常单调的过程， 细胞外基质（ECM）导致广泛的组织纤维化。因此，在本发明中， 开发一种抑制纤维化的方案似乎是 慢性肾脏病的治疗我们实验室的初步研究 提示肝细胞生长因子（HGF）是一种重要调节因子， 细胞外基质周转导致组织纤维化的抑制 肾脏疾病动物模型。因为外源性HGF在血液中非常不稳定 由于肝脏的快速清除，我们最近开发了一种基因， 使用裸质粒载体的转移策略导致有效表达 HGF蛋白的表达。基于这些结果，我们假设， HGF基因是治疗慢性胰腺炎的有效策略。 肾脏疾病在本申请中，我们提出将HGF基因施用到 进行性肾病动物模型，以评价其治疗效果。 我们将通过以下方法研究HGF改善肾纤维化的机制： 检查肌成纤维细胞活化和TGF-β 1信号传导的调节。 这些将在以下三个具体目标中实现：1）评估 HGF基因治疗慢性肾纤维化的疗效; 2）探讨 HGF在肾成肌纤维细胞活化中的作用; 3）阐明HGF在肾成肌纤维细胞活化中的作用。 HGF阻断促纤维化细胞因子TGF-β 1的分子机制 发信号。这些研究将提供基本信息，如 HGF基因治疗慢性肾脏疾病的可行性和有效性， 将最终导致新的治疗策略，以人类慢性肾脏病 纤维化，这是不可治愈的。