Role of Acetyl CoA carboxylase in type 2 diabetic kidney disease

摘要： 背景：我们早期的人类观察研究表明，在2型糖尿病肾病进展过程中，新生脂肪生成(DNL)上调与肾脏乙酰辅酶A羧基酶(ACC)编码基因ACACA和ACACB上调有关，提示肾脏DNL上调可能是2型糖尿病肾病进展的机制之一。本项目的目标是在足细胞和近端肾小管上皮细胞中建立条件敲除AcacA和Acacb的转基因小鼠模型，目的是在R01拨款申请的未来研究课题中，与野生型糖尿病小鼠模型进行比较，测试敲除体内模型系统中肾功能和结构组织学的保存情况。方法：我们将利用129SVE背景的ACC1/2 FLOX小鼠与Podocin-Cre和PEPCK-Cre小鼠杂交的育种方案。结果：预计到本项目结束时，我们将在足细胞和近端肾小管上皮细胞中建立有条件地敲除ACC1/2的糖尿病小鼠模型，然后准备在下游研究中测试其对DKD的保护作用。

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.