Renal Fibrosis in Diabetes

糖尿病肾纤维化

基本信息

批准号：
8443317
负责人：
HANNA E ABBOUD
金额：
--
依托单位：
SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-10-01 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8443317
关键词：
Active Sites Animals Cells Characteristics Collagen Type IV Complications of Diabetes Mellitus Data Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse E-Cadherin Epithelial Epithelial Cells Epithelium Fibronectins Fibrosis Genetic Genetic Transcription Glucose Heterozygote In Vitro Injury Insulin-Dependent Diabetes Mellitus Kidney Kidney Diseases Mediating Mediator of activation protein Mesenchymal Metabolic Control Metformin Mus Normal Cell Pathogenesis Pathway interactions Phosphorylation Phosphotransferases Protein Isoforms Proteins Ribosomal Protein S6 Kinase Role Signal Pathway Signal Transduction Signal Transduction Pathway Sirolimus Site Smooth Muscle Actin Staining Method Tissues Transcriptional Regulation Transforming Growth Factor beta Translations Tubular formation Tumor Suppressor Proteins Work cell injury diabetic human FRAP1 protein human TSC2 protein in vivo inhibitor/antagonist interstitial kidney cortex mTOR Inhibitor novel therapeutics prevent protein expression public health relevance response sensor

Active Sites Animals Cells Characteristics Collagen Type IV Complications of Diabetes Mellitus Data Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse E-Cadherin Epithelial Epithelial Cells Epithelium Fibronectins Fibrosis Genetic Genetic Transcription Glucose Heterozygote In Vitro Injury Insulin-Dependent Diabetes Mellitus Kidney Kidney Diseases Mediating Mediator of activation protein Mesenchymal Metabolic Control Metformin Mus Normal Cell Pathogenesis Pathway interactions Phosphorylation Phosphotransferases Protein Isoforms Proteins Ribosomal Protein S6 Kinase Role Signal Pathway Signal Transduction Signal Transduction Pathway Sirolimus Site Smooth Muscle Actin Staining Method Tissues Transcriptional Regulation Transforming Growth Factor beta Translations Tubular formation Tumor Suppressor Proteins Work cell injury diabetic human FRAP1 protein human TSC2 protein in vivo inhibitor/antagonist interstitial kidney cortex mTOR Inhibitor novel therapeutics prevent protein expression public health relevance response sensor

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项目摘要

DESCRIPTION (provided by applicant): Tubulointerstitial fibrosis is a prominent pathological feature of progressive renal disease including diabetic nephropathy. In diabetic nephropathy and other progressive renal diseases, tubular epithelial cells acquire mesenchymal cell characteristics and accumulate matrix proteins that eventuate in fibrosis. Two potential mediators of renal fibrosis in diabetes are high glucose concentrations and transforming growth factor-beta. We have evidence that glucose and TGF-beta inactivate the energy sensor AMPK and that this may result in the cells acquiring mesenchymal cell characteristics and accumulating matrix proteins. The work proposed in this application will utilize in vitro and in vivo approaches to establish if AMPK is indeed a modulator of renal fibrosis and identify downstream signal transduction pathway(s) that may be the effectors of AMPK. Pharmacological and genetic approaches will be used to activate or inhibit AMPK in vitro in cultured tubular epithelial cells and in vivo. For the in vivo studies, we will utlize mice deficient in AMPK specifically in proximal tubular cells. In addition, OVE26 mice with type 1 diabetes will be used to investigate the role of AMPK and downstream signaling pathways including tuberin and mTOR. The central hypothesis of this proposal is that AMPK regulates matrix protein accumulation and mesencymal characteristics of tubular epithelium in diabetes through translational or transcriptional pathways. The studies will help establish adjunct therapy in addition to metabolic control to treat the complications of diabetes.

描述（由申请人提供）：微管间质纤维化是进行性肾脏疾病在内的重要病理特征，包括糖尿病性肾病。在糖尿病性肾病和其他进行性肾脏疾病中，管状上皮细胞获得了间质细胞特征，并积累了在纤维化中发生的基质蛋白。糖尿病中肾纤维化的两个潜在介体是高葡萄糖浓度和转化生长因子β。我们有证据表明葡萄糖和TGF-β使能量传感器AMPK失活，这可能导致细胞获得间充质细胞特性并积累基质蛋白。本应用程序中提出的工作将利用体外和体内方法来确定AMPK是否确实是一个调节剂肾纤维化并确定可能是AMPK效应子的下游信号转导途径。药理和遗传方法将用于激活或抑制培养的管状上皮细胞和体内的AMPK。对于体内研究，我们将专门在近端管状细胞中解除缺乏AMPK的小鼠。此外，具有1型糖尿病的OVE26小鼠将用于研究AMPK和下游信号通路的作用，包括Tuberin和MTOR。该提案的中心假设是AMPK调节糖尿病中肾小管上皮的基质蛋白的积累和通过翻译或转录途径的中性特征。这些研究还将有助于建立辅助疗法，除了代谢控制以治疗糖尿病并发症。