The objective of the proposed research is to gain insight into potential mediators and pathogenic mechanisms responsible for the development and progression of radiation nephropathy, thereby providing a scientific basis for the rational design and later application of interventional therapies attenuating the severity of this dose-limiting normal tissue morbidity. The working hypothesis of this proposal is that irradiation induces over expression of the intra renal renin angiotensin system (RAS) and the fibrogenic cytokine transforming growth factor-beta. These act in an autocrine and paracrine manner to alter the mesangial cell (MC) phenotype in particular, with resultant over expression of extracellular matrix (ECM) gene products leading to glomerulosclerosis, loss of functioning nephrons, and ultimate renal failure. The application of regimens designed to selectively increase or decrease the severity of radiation nephropathy will be associated with a concomitant up regulation or down regulation, respectively of the RAS, TGF-beta, and ECM gene products. The proposal will test this hypothesis using four specific aims. The ability to reduce the severity of radiation nephropathy would have significant impact in cancer therapy. Thus, a thorough understanding of the specific mediators and mechanisms involved in experimental radiation nephropathy offers the promise of ultimately developing rational therapeutic strategies targeted at reducing the severity of this lesion in human beings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK051612-01A1
Application #
2017357
Study Section
Radiation Study Section (RAD)
Project Start
1997-05-01
Project End
2000-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Iowa
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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