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之一，发病率和死亡率都很高，全球范围内患者数量呈上升趋势。本次竞争性更新申请是我们长期努力的延续，旨在为进展为ESRD的慢性肾脏疾病（CKD）的治疗干预制定合理策略。尽管主要病因多种多样，但CKD的发病机制的特征在于慢性炎性浸润和细胞外基质（ECM）的持续积累，导致广泛的组织纤维化。因此，开发抑制炎症和纤维化的方案可能是治疗CKD的关键策略。本申请前期项目期间的研究表明，肝细胞生长因子（HGF）是有效的抗纤维化、抗炎因子，可预防动物模型中CKD的发生和进展。在这个延续的申请中，我们建议研究HGF发挥其有益作用的分子机制。待检验的中心假设是：1）HGF通过拮抗TGF-β/Smad信号传导的纤维化作用来抑制肾纤维化; 2）HGF通过阻断促炎性NF-κ B信号传导来抑制肾炎症;以及3）HGF与TGF-β 1协同作用以抑制肾炎症。这些假说将分别从整体动物、细胞、信号转导和分子水平三个具体目标来阐述。目的1探讨HGF诱导肾小管上皮细胞SnoN表达的分子机制，并评价SnoN基因转染对慢性肾纤维化的治疗作用。目的二是了解HGF阻断肾脏炎症和NF-kB信号转导的机制，并研究HGF和TGF-β 1之间的相互作用导致肾脏炎症的协同抑制。目的3探讨HGF/c-met信号通路在过氧化物酶体增殖物激活受体-γ抗肝纤维化作用中的作用。这些研究将为理解HGF治疗CKD的机制提供基础和重要的见解。最终，这些研究可能导致开发新的策略，通过操纵HGF信号系统的活性来改变人类肾脏疾病的进程。

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.