? In our previous work we have demonstrated that genetic factors controlling the production of bradykinin (BK) and nitric oxide (NO) influence greatly the development of renal complications in mice made diabetic with streptozotocin (STZ) or by the Akita diabetogenic C86Y mutation in Ins 2. We also showed that diabetic nephropathy and several indicators of senescence increase progressively in the order wildtype < bradykinin receptor B2 null < Akita diabetic < B2 receptor null Akita diabetic. 8-OHdG content, point mutations and deletions in mitochondrial (mt) DNA increased in the same progression, as did indicators of oxidative stress. We now propose three specific aims and the generation of two new mouse models to determine the interplay between genetic factors that influence BK action, the production of NO, and diabetes-related increases in mutations in mtDNA.
Specific aim 1 will determine the effect on diabetic complications of eliminating both BK receptors throughout the body, or in a tissue or cell specific manner; the effects of reducing oxidative stress in these mice will also be determined.
Specific aim 2 will investigate the relationship between glomerular damage and mtDNA mutations in eNOS -/- diabetic mice in which we have found that oxidative stress is paradoxically less than in eNOS +/+ diabetic mice.
Specific aim 3 will test the hypothesis that increasing the frequency of mtDNA mutations by introducing a proof reading defect into mitochondrial DNA polymerase gamma will exacerbate the complications in Akita diabetic mice even though oxidative stress is not further increased over that due to the diabetes alone. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01DK076131-01
Application #
7151271
Study Section
Special Emphasis Panel (ZDK1-GRB-4 (M1))
Program Officer
Ketchum, Christian J
Project Start
2006-09-30
Project End
2011-08-31
Budget Start
2006-09-30
Budget End
2007-08-31
Support Year
1
Fiscal Year
2006
Total Cost
$273,750
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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