HGF Gene Therapy for Chronic Renal Fibrosis

HGF基因治疗慢性肾纤维化

• 批准号: 7091862
• 负责人: YOUHUA LIU
• 金额: $ 27.16万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091862
• 关键词: biological signal transduction; chronic renal failure; disease /disorder model; disease /disorder prevention /control; enzyme linked immunosorbent assay; fibrogenesis; fibrosis; gene delivery system; gene expression; gene induction /repression; gene therapy; genetically modified animals; hepatocyte growth factor; immunocytochemistry; inflammation; intermolecular interaction; laboratory mouse; nonhuman therapy evaluation; peroxisome proliferator activated receptor; polymerase chain reaction; transcription factor; 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. This competitive renewal application is a continuation of our long-term efforts to develop rational strategies for therapeutic intervention of chronic kidney diseases (CKD) that progress to ESRD. Despite diverse primary etiologies, the pathogenesis of CKD is characterized by chronic inflammatory infiltration and relentless accumulation of extracellular matrix (ECM) leading to widespread tissue fibrosis. Thus, developing a scheme to inhibit inflammation and fibrosis may be a key strategy for the treatment of CKD. Studies in previous project period of this application suggest that hepatocyte growth factor (HGF) is potent anti-fibrotic, anti-inflammatory factor that prevents the onset and progression of CKD in animal models. In this continuation application, we propose to investigate the molecular mechanism by which HGF elicits its beneficial actions. The central hypotheses to be tested are that: 1) HGF inhibits renal fibrosis by antagonizing the fibrogenic action of TGF-¿/Smad signaling; 2) HGF suppresses renal inflammation by blocking pro-inflammatory NF-kB signaling; and 3) HGF interacts synergistically with TGF-¿1 to suppress renal inflammation. These hypotheses will be addressed by three specific aims at the whole animal, the cellular, the signal transduction and molecular levels, respectively. Aim 1 is designed to investigate the molecular mechanism underlying HGF induction of SnoN expression in tubular epithelial cells and to evaluate the therapeutic efficacy of SnoN gene transfer for chronic kidney fibrosis in vivo. Aim 2 is to understand the mechanism underlying HGF blockade of renal inflammation and NF-kB signaling and investigate the interplay between HGF and TGF-¿1 leading to synergistic inhibition of renal inflammation. Aim 3 is to evaluate the role of HGF/c-met signaling in mediating the anti-fibrotic action of peroxisome proliferator- activated receptor-y. These studies will provide fundamental and important insights into understanding the mechanism underlying the therapeutic efficacy of HGF for CKD. Ultimately, these studies may lead to development of novel strategies to alter the course of human kidney disease by manipulating the activity of HGF signaling system.

终末期肾病（End-stage renal disease， ESRD）是世界上最具破坏性的疾病之一，发病率和死亡率都很高，在世界范围内患者数量呈上升趋势。这项竞争性更新申请是我们长期努力为进展为ESRD的慢性肾脏疾病（CKD）制定合理的治疗干预策略的延续。尽管原发性病因多种多样，但CKD的发病机制以慢性炎症浸润和细胞外基质（ECM）的持续积累为特征，导致广泛的组织纤维化。因此，开发一种抑制炎症和纤维化的方案可能是治疗慢性肾病的关键策略。本项目前期的研究表明，肝细胞生长因子（HGF）是一种有效的抗纤维化、抗炎因子，在动物模型中可以阻止CKD的发生和发展。在这一继续应用中，我们建议研究HGF引发其有益作用的分子机制。待验证的中心假设为：1)HGF通过拮抗TGF-¿/Smad信号的成纤维作用抑制肾纤维化；2) HGF通过阻断促炎NF-kB信号通路抑制肾脏炎症；3) HGF与TGF-¿1协同作用抑制肾脏炎症。这些假设将分别从动物整体水平、细胞水平、信号转导水平和分子水平三个方面进行阐述。Aim 1旨在研究HGF诱导小管上皮细胞SnoN表达的分子机制，并评估SnoN基因转移治疗慢性肾纤维化的体内疗效。目的2是了解HGF阻断肾炎症和NF-kB信号传导的机制，并研究HGF与TGF-¿1之间的相互作用，从而协同抑制肾炎症。目的3是评估HGF/c-met信号在介导过氧化物酶体增殖物激活受体的抗纤维化作用中的作用。这些研究将为理解HGF治疗慢性肾病疗效的机制提供基础和重要的见解。最终，这些研究可能会导致通过操纵HGF信号系统的活性来改变人类肾脏疾病进程的新策略的发展。