This project is based on the hypothesis that renal injury will occur after certain types of radiological terrorism events, and that this injury can be both mitigated and treated. We are using the convention adopted by recent NCI workshops that: """"""""mitigation"""""""" refers to therapies that are effective when begun after irradiation, but before there is pathophysiological evidence of radiation injury; and """"""""treatment"""""""" refers to therapies which are effective when begun after pathophysiological evidence of radiation injury is present. We have used a rat total body irradiation (TBI) model to demonstrate that angiotensin converting enzyme (ACE) inhibitors and angiotensin II (All) type-1 receptor antagonists (AT1 blockers) are effective for the mitigation and treatment of radiation-induced renal injury. Our previous studies have used the types of fractionated high-dose-rate radiation schedules that are used in radiation oncology and bone marrow transplantation (BMT), have been oriented towards understanding the pathophysiological basis of the injury, and have often used agents that are not yet approved for human use. The proposed studies will use the types of radiation schedules most likely to present in radiological terrorism events (single doses at high or low dose rates) and will focus on developing products suitable for clinical use.
The specific aims of this proposal are to: demonstrate that captopril (an FDA-approved ACE inhibitor) and losartan (an FDA-approved AT1 blocker) can be used to both mitigate and treat the radiation-induced renal injuries that could arise from radiological terrorism; determine whether these agents are acting via suppression of chronic oxidative stress; and determine whether an in vitro glomerular leakage assay can be used as a high through-put screening tool for finding new mitigators of radiation-induced renal injury. In summary, experimental studies suggest radiation-induced renal injury can be treated. The goal of this project is to bring one or more of these experimental approaches into clinical practice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI067734-02
Application #
7310392
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$375,930
Indirect Cost
Name
Medical College of Wisconsin
Department
Type
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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Medhora, Meetha; Gao, Feng; Glisch, Chad et al. (2015) Whole-thorax irradiation induces hypoxic respiratory failure, pleural effusions and cardiac remodeling. J Radiat Res 56:248-60
Moulder, John E; Cohen, Eric P; Fish, Brian L (2014) Mitigation of experimental radiation nephropathy by renin-equivalent doses of angiotensin converting enzyme inhibitors. Int J Radiat Biol 90:762-8
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Medhora, Meetha; Gao, Feng; Wu, Qingping et al. (2014) Model development and use of ACE inhibitors for preclinical mitigation of radiation-induced injury to multiple organs. Radiat Res 182:545-55
Mahmood, Javed; Jelveh, Salomeh; Zaidi, Asif et al. (2014) Targeting the Renin-angiotensin system combined with an antioxidant is highly effective in mitigating radiation-induced lung damage. Int J Radiat Oncol Biol Phys 89:722-8
Moulder, John E (2014) 2013 Dade W. Moeller lecture: medical countermeasures against radiological terrorism. Health Phys 107:164-71

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