The Duke-UNC-Stanford Center for Mouse Models of Diabetic Complications consists of a multi-disciplinary group of investigators with substantial experience in genetic engineering, in molecular and physiological phenotyping in mice, and in the study of rodent models of diabetes. Based on our cumulative expertise, we propose to study two diabetic complications: nephropathy and vascular disease. We recognize the deficiencies of current mouse models of diabetic complications including relatively mild severity that does not progress to recapitulate the pathology seen in the later stages of human diabetes. We hypothesize that this lack of congruity with human disease is not due to a fundamental difference in biology, but instead is due to the presence or absence of genetic factors that modulate susceptibility to end-organ injury. Therefore, in our proposals for model development, we will introduce genetic alterations into diabetic mice with the aim of exaggerating the severity of kidney and vascular disease. These proposed alterations fall into two categories. First are genetic changes that cause hypertension. Hypertension is a common accompaniment of diabetes and control of blood pressure can ameliorate the development of diabetic complications in humans. Our genetic hypertension models differ in the level of involvement of the renin-angiotensin system so that the actions of elevated blood pressure can be separated from those of angiotensin II. Secondly, we will generate diabetic mice with genetic alterations that enhance formation or actions of reactive oxygen species, another pathway that has been suggested to promote human diabetic complications. To achieve our aims of developing and characterizing mouse models of diabetic complications, we also propose three technical innovations: (1) To generate embryonic stem cell lines from diabetic mouse strains to facilitate genetic manipulation. (2) To produce mice with """"""""humanized"""""""" susceptibility loci for diabetic complications as they are identified in human genetic studies. (3) To develop molecular phenotyping for sensitive detection of changes in gene expression associated with diabetic end-organ damage. We plan to share these technologies fully with other investigators to help accomplish the overall goals of the Mouse Models of Diabetic Complications Consortium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL070523-03
Application #
6654894
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (O2))
Program Officer
Rabadan-Diehl, Cristina
Project Start
2001-09-30
Project End
2006-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
3
Fiscal Year
2003
Total Cost
$729,001
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Hathaway, Catherine K; Chang, Albert S; Grant, Ruriko et al. (2016) High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy. Proc Natl Acad Sci U S A 113:2218-22
Hathaway, Catherine K; Gasim, Adil M H; Grant, Ruriko et al. (2015) Low TGF?1 expression prevents and high expression exacerbates diabetic nephropathy in mice. Proc Natl Acad Sci U S A 112:5815-20
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Takahashi, N; Boysen, G; Li, F et al. (2007) Tandem mass spectrometry measurements of creatinine in mouse plasma and urine for determining glomerular filtration rate. Kidney Int 71:266-71

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