Role of Acetyl CoA carboxylase in type 2 diabetic kidney disease

乙酰辅酶A羧化酶在2型糖尿病肾病中的作用

• 批准号: 10252084
• 负责人: Farsad Afshinnia
• 金额: $ 10.14万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252084
• 关键词: Acetyl-CoA Carboxylase; Animals; Applications Grants; Backcrossings; Biological Models; Breeding; Chronic Kidney Failure; Complex; Coupled; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Dietary Fatty Acid; Dietary Intervention; Disease Progression; Enzymes; Epithelial Cells; Fatty Acids; Generations; Genes; Goals; Histology; Human; Kidney; Kidney Diseases; Knock-in; Knock-out; Link; Lipids; Methods; Modeling; Mus; NPHS2 protein; Non-Insulin-Dependent Diabetes Mellitus; Observational Study; Outcome; Palmitates; Patients; Polyunsaturated Fatty Acids; Renal function; Research; Research Subjects; Role; Scheme; Structure; Testing; Transgenic Mice; Tubular formation; Type 2 diabetic; Up-Regulation; acylcarnitine; conditional knockout; diabetic; improved; in vivo Model; kidney preservation; lipid biosynthesis; mouse model; podocyte; preservation; protective effect

Abstract: Background: Our earlier human observational studies showed upregulation of de novo lipogenesis (DNL) linked with upregulation of renal acetyl-CoA carboxylase (ACC) encoding genes ACACA and ACACB in progressors of diabetic kidney disease with type 2 diabetes, suggesting that upregulation of renal DNL might be a mechanism of diabetic kidney disease progression in type 2 diabetes. The goal of this project is to generate a transgenic mouse model with conditional knocked out Acaca and Acacb in podocytes and proximal tubular epithelial cells aimed at testing the preservation of renal function and structural histology in the knocked out in vivo model system compared with the wild type diabetic mouse model in future research subject of R01 grant application. Methods: We will utilize a breeding scheme consisting of cross breeding of ACC1/2 flox mice with podocin-Cre and Pepck-Cre mice all on 129SVE background. Outcome: It is expected that by the end of this project we will generate a diabetic mouse model with conditionally knocked out ACC1/2 in podocytes and proximal tubular epithelial cells which then will be ready to test its protective effect against DKD in downstream research.

摘要： 工作背景：我们早期的人体观察性研究显示，在2型糖尿病肾病进展者中，从头脂肪生成（DNL）上调与肾乙酰辅酶A羧化酶（ACC）编码基因ACACA和ACACB上调相关，这表明肾DNL上调可能是2型糖尿病肾病进展的机制。本项目的目标是在足细胞和近端肾小管上皮细胞中产生条件性敲除Acaca和Acacb的转基因小鼠模型，旨在测试R 01资助申请的未来研究课题中与野生型糖尿病小鼠模型相比，敲除体内模型系统中肾功能和结构组织学的保留。研究方法：我们将利用由ACC 1/2 flox小鼠与podocin-Cre和Pepck-Cre小鼠的杂交育种组成的育种方案，所有小鼠都在129 SVE背景下。结果：预计到本项目结束时，我们将产生足细胞和近端肾小管上皮细胞中条件性敲除ACC 1/2的糖尿病小鼠模型，然后将准备在下游研究中测试其对DKD的保护作用。