Abdominal radiation therapy is often dose-limited by the risk of intestinal toxicity (radiation enteropathy). Radiation enteropathy is associated with consistent and sustained transforming growth factor b (TGF-b) overexpression in areas that display structural injury. This project tests the hypotheses that 1) TGF-b overexpression is an independent predictor of radiation enteropathy, 2) Modulation of post-radiation TGF-b levels affects development of chronic radiation-induced lesions and complications, 3) TGF-b plays a more significant role in consequential radiation enteropathy (chronic injury secondary to mucosal break-down) than in primary radiation enteropathy (chronic injury without mucosal disruption), and 4) interactions between mast cells and TGF-b are important in the mechanism of chronicity. A loop of small bowel is surgically attached in the scrotum of male rats. The intestine in the """"""""scrotal hernia"""""""" is subsequently irradiated, producing intestinal complications and morphologic lesions similar to those seen clinically. TGF-b expression and histopathologic, cellular, morphometric, and functional changes are assessed up to 26 weeks after irradiation.
Specific aims are to 1) assess quantitative associations between TGF-b expression, radiation dose, observation time, and parameters of intestinal toxicity, 2) determine if adding TGF-b during the acute phase of injury increases the severity of subsequent radiation enteropathy, 3) determine if neutralization of TGF-b during the acute phase of injury ameliorates subsequent chronic radiation enteropathy, 4) compare TGF-b expression in consequential versus primary radiation enteropathy, and 5) assess TGF-b expression and severity of radiation enteropathy in mast cell-deficient rats compared to mast cell-competent litter-mates. Results from these experiments will provide significant new information regarding the molecular pathogenesis of radiation enteropathy. An improved understanding of these mechanisms will facilitate development of treatment protocols and interventions to minimize intestinal toxicity, and thus has potential to improve the therapeutic ratio of radiation therapy in patients with abdominal tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA071382-04
Application #
6164219
Study Section
Radiation Study Section (RAD)
Program Officer
Stone, Helen B
Project Start
1997-05-01
Project End
2001-08-31
Budget Start
2000-03-01
Budget End
2001-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$208,861
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Little Rock
State
AR
Country
United States
Zip Code
72205
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Sridharan, Vijayalakshmi; Aykin-Burns, Nukhet; Tripathi, Preeti et al. (2014) Radiation-induced alterations in mitochondria of the rat heart. Radiat Res 181:324-34
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Hauer-Jensen, Martin (2014) Toward development of interleukin-11 as a medical countermeasure for use in radiological/nuclear emergencies. Dig Dis Sci 59:1349-51
Zhou, Daohong; Shao, Lijian; Spitz, Douglas R (2014) Reactive oxygen species in normal and tumor stem cells. Adv Cancer Res 122:1-67
Sridharan, Vijayalakshmi; Tripathi, Preeti; Sharma, Sunil et al. (2014) Roles of sensory nerves in the regulation of radiation-induced structural and functional changes in the heart. Int J Radiat Oncol Biol Phys 88:167-74
Pathak, R; Shao, L; Chafekar, S M et al. (2014) IKK? regulates endothelial thrombomodulin in a Klf2-dependent manner. J Thromb Haemost 12:1533-1544
Pathak, Rupak; Pawar, Snehalata A; Fu, Qiang et al. (2014) Characterization of transgenic Gfrp knock-in mice: implications for tetrahydrobiopterin in modulation of normal tissue radiation responses. Antioxid Redox Signal 20:1436-46
Garg, Sarita; Wang, Wenze; Prabath, Biju G et al. (2014) Bone marrow transplantation helps restore the intestinal mucosal barrier after total body irradiation in mice. Radiat Res 181:229-39

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