HGF Gene Therapy for Chronic Renal Fibrosis

HGF基因治疗慢性肾纤维化

• 批准号: 7393665
• 负责人: YOUHUA LIU
• 金额: $ 25.84万
• 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/7393665
• 关键词: Abbreviations; Address; Affect; Agonist; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; CREB1 gene; Cells; Chronic; Chronic Kidney Failure; Cyclic AMP-Responsive DNA-Binding Protein; Data; Development; Disease; End stage renal failure; Epithelial; Epithelial Cells; Etiology; Exhibits; Extracellular Matrix; Factor V; Fibroblasts; Fibrosis; Gene Transfer; Genes; Genetic Transcription; Glycogen Synthase Kinases; Goals; Growth Factor Gene; Growth Factor Inhibition; Hepatocyte Growth Factor; Human; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Kidney; Kidney Diseases; Laboratories; Lead; Mediating; Mitogen-Activated Protein Kinase 3; Molecular; Morbidity - disease rate; Myofibroblast; NF-kappa B; Nuclear; Numbers; Pathogenesis; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phosphatidylinositols; Phosphotransferases; Prevention strategy; Research; Research Personnel; Role; Scheme; Signal Pathway; Signal Transduction; Smooth Muscle Actin Staining Method; Staging; System; T-Lymphocyte; Testing; Therapeutic Agents; Therapeutic Intervention; Tissues; Transcription Repressor/Corepressor; Transforming Growth Factors; Treatment Efficacy; Tubular formation; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Ureteral obstruction; Work; cytokine; design; epithelial to mesenchymal transition; gene therapy; human TNF protein; in vivo; insight; interstitial; kidney cell; mortality; novel strategies; prevent; programs

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.

描述(申请人提供)：终末期肾病(ESRD)是最具破坏性的疾病之一，具有极高的发病率和死亡率，全球患者数量呈上升趋势。这一竞争性续签申请是我们长期努力的延续，目的是为进展为终末期肾病的慢性肾脏疾病(CKD)的治疗干预制定合理的策略。尽管病因多种多样，但CKD的发病机制以慢性炎症浸润和细胞外基质(ECM)的持续堆积为特征，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CKD的关键策略。本应用前期项目期的研究表明，肝细胞生长因子(HGF)是一种有效的抗纤维化、抗炎因子，可在动物模型中防止CKD的发生和发展。在接下来的应用中，我们建议研究HGF产生其有益作用的分子机制。需要检验的中心假设是：1)HGF通过拮抗转化生长因子β/Smad信号的促纤维化作用来抑制肾纤维化；2)HGF通过阻断促炎因子-kB信号来抑制肾脏炎症；以及3)HGF与转化生长因子β1协同作用抑制肾脏炎症。这些假说将分别针对整个动物、细胞、信号转导和分子水平的三个特定目标来解决。目的1研究肝细胞生长因子(HGF)诱导肾小管上皮细胞表达SnoN的分子机制，评价SnoN基因转移对慢性肾纤维化的治疗作用。目的2了解肝细胞生长因子(HGF)阻断肾组织炎症及核因子-kB信号转导的机制，探讨HGF与转化生长因子-β1协同抑制肾组织炎症的作用。目的3探讨HGF/c-MET信号转导途径在介导过氧化物酶体增殖物激活受体-y抗纤维化作用中的作用。这些研究将为理解HGF治疗CKD的潜在机制提供基本和重要的见解。最终，这些研究可能会导致开发新的策略，通过操纵HGF信号系统的活性来改变人类肾脏疾病的进程。