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Generating Mouse Mutants with Diabetic Nephropathy

产生患有糖尿病肾病的小鼠突变体

基本信息

批准号：
7907861
负责人：
RAYMOND C. HARRIS
金额：
$ 34.41万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7907861
关键词：
Acceleration Acetylcholine Address Albuminuria Alleles Animal Model Apolipoprotein E Attention Biochemical Pathway C57BL/6 Mouse Cardiovascular Diseases Cardiovascular system Cessation of life Clinical Research Complications of Diabetes Mellitus Development Diabetic Nephropathy Dissection Endothelial Cells Endothelium Enzymes Event Excretory function Exhibits Functional disorder Funding Genes Genetic Genetic Polymorphism Genotype Goals Guidelines Human Hyperglycemia Inbred Strain Injury Kidney Diseases Kidney Failure Link Maintenance Microalbuminuria Modeling Mus Mutant Strains Mice Neuropathy Oxidative Stress PTGS2 gene Pathogenesis Pathway interactions Peroxonitrite Play Prostacyclin synthase Prostaglandins I Renal function Research Personnel Resistance Retinal Diseases Risk Role Site Source Structure Testing Vasodilation clinically relevant diabetic enzyme activity human NOS3 protein human disease macrovascular disease man mortality mouse model novel therapeutics prevent programs resistant strain type I diabetic urinary

项目摘要

DESCRIPTION (provided by applicant): The goal of the AMDCC is to develop animal models of diabetic complications that faithfully reproduce diabetic complications observed in humans. This proposal will provide a model of mouse model of diabetic nephropathy (DN) focusing on two key protective endothelial pathways: eNOS and prostacyclin synthase (PGIS). These pathways are not only co-localized within the endothelial cells but their activity is also biochemically interrelated through cellular levels of peroxynitrate, and both that have been implicated in human diabetic nephropathy, neuropathy, retinopathy and macrovascular disease. In the previous funding cycle, the Vanderbilt AMDCC site investigated the genetic underpinnings of diabetic nephropathy (DN) of mice. Those studies identified systemic eNOS deletion as a critical genetic modifier that converts C57BL/6 mice from a resistant strain to one that is susceptible to DN. Genetic disruption of endothelial nitric oxide synthase (eNOS or NOSIII), but not ApoE or LDLR was associated with a marked acceleration of DN in C57BL/6, not only characterized by a robust albuminuria, but also by dramatic mesangiolysis and expansion with decrease renal function (GFR). The involvement of eNOS as a clinically relevant modifier for risk of human diabetic nephropathy is bolstered by clinical studies showing that diabetics with an eNOS Glu298Asp polymorphism not only exhibit decreased eNOS activity but also an accelerated risk of renal failure {Noiri, 2002 #6975; Shin Shin, 2004 #8934}. Accumulating evidence implicates endothelial dysfunction in the pathogenesis of diabetic complications, particularly nephropathy and macrovascular disease {Schalkwijk, 2005 #9302}. Similarly polymorphisms have been identified in prostacyclin synthase (PGIS), although their specific role in the progression of diabetic nephropathy has not been established, The present proposal has two specific aims: Aim 1 will determine the role of endothelial eNOS in the progression of diabetic nephropathy; while To determine the role of Endothelial prostacyclin synthase in the progression of diabetic nephropathy. To achieve this we will generate conditionally targeted (floxed) eNOS and PGIS alleles, and cross these mice with a Tie2mERCre mouse, allowing temporally controlled deletion of these alleles specifically from the endothelium. These studies should allow the dissection of the role of these biochemical pathways in the progression of diabetic nephropathy in mice.

描述（由申请人提供）：

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bladder dysfunction in mice with experimental autoimmune encephalomyelitis.

DOI：
10.1016/j.jneuroim.2008.06.038
发表时间：
2008-10-15
期刊：
Journal of neuroimmunology
影响因子：
3.3
作者：
Altuntas CZ;Daneshgari F;Liu G;Fabiyi A;Kavran M;Johnson JM;Gulen MF;Jaini R;Li X;Frenkl TL;Tuohy VK
通讯作者：
Tuohy VK

Examining diabetic nephropathy through the lens of mouse genetics.

DOI：
10.1007/s11892-007-0078-3
发表时间：
2007-12-01
期刊：
Current diabetes reports
影响因子：
4.2
作者：
Breyer, Matthew D;Tchekneva, Elena;Harris, Raymond C
通讯作者：
Harris, Raymond C

Genetics of diabetic nephropathy: lessons from mice.

糖尿病肾病的遗传学：来自小鼠的教训。

DOI：
10.1016/j.semnephrol.2007.01.001
发表时间：
2007
期刊：
Seminars in nephrology
影响因子：
3.3
作者：
Breyer,MatthewD;Tchekneva,Elena;Qi,Zhonghua;Takahashi,Takamune;Fogo,AgnesB;Zhao,HuiJohn;Harris,RaymondC
通讯作者：
Harris,RaymondC

Insight into the genetics of diabetic nephropathy through the study of mice.

通过对小鼠的研究深入了解糖尿病肾病的遗传学。