Abdominal radiation therapy is often dose-limited by the risk of intestinal toxicity (radiation enteropathy). Radiation enteropathy is characterized by epithelial barrier breakdown and mucosal inflammation, and subsequent development of progressive fibrosis and vascular sclerosis. Microvascular injury is believed to promote radiation enteropathy development, but molecular links have not yet been established in vivo. Clinical and preclinical studies performed by the PI strongly suggest that radiation-induced endothelial dysfunction, notably loss of vascular thromboresistance due to deficient thrombomodulin (TM) expression, is mechanistically involved in radiation enteropathy development. TM is an endothelial cell protein that modulates thrombin's functions, and essentially converts thrombin from a pro-coagulant to an anticoagulant. After irradiation, deficient levels of TM lead to increased formation of thrombin. Thrombin, in addition to its key role in coagulation, also regulates inflammation and fibrosis. This research project uses validated, genetically modified animal models and pharmacologic compounds, along with quantitative molecular methods, to systematically examine, in vivo, a) the relative significance of thrombin's various effects in context of the intestinal radiation response, and b) endothelial-directed interventions aimed at ameliorating radiation enteropathy. Specifically, the project will 1) examine whether fibrin deposition adversely affects intestinal radiation fibrosis;2) investigate whether blocking the cellular thrombin receptor, proteinase-activated receptor 1, ameliorates radiation enteropathy;3) assess whether exogenous administration of activated protein C, an anticoagulant and anti-inflammatory mediator that is activated by thrombin in the presence of TM, influences the intestinal radiation response;4) test whether statins, a commonly used class of cholesterol-lowering drugs with vasculoprotective effects, ameliorate chronic intestinal radiation fibrosis;and 5) determine whether the enteroprotective effect of statins requires upregulation of TM. These studies will provide substantial new insight into the basic pathogenesis of the intestinal radiation response. A comprehensive understanding of these underlying mechanisms is critical for identifying clinically relevant targets for intervention. This project may thus facilitate development of specific strategies to minimize intestinal radiation toxicity, thereby making radiation therapy safer and more effective.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083719-10
Application #
7610995
Study Section
Special Emphasis Panel (ZRG1-ONC-K (02))
Program Officer
Wong, Rosemary S
Project Start
2000-07-01
Project End
2012-04-30
Budget Start
2009-05-01
Budget End
2012-04-30
Support Year
10
Fiscal Year
2009
Total Cost
$286,114
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Surgery
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
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Wang, Junru; Boerma, Marjan; Kulkarni, Ashwini et al. (2010) Activation of protease activated receptor 2 by exogenous agonist exacerbates early radiation injury in rat intestine. Int J Radiat Oncol Biol Phys 77:1206-12
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Vural, Emre; Berbée, Maaike; Acott, Alison et al. (2010) Skin graft take rates, granulation, and epithelialization: dependence on myeloid cell hypoxia-inducible factor 1alpha. Arch Otolaryngol Head Neck Surg 136:720-3
Owings, Richard A; Boerma, Marjan; Wang, Junru et al. (2009) Selective deficiency of HIF-1alpha in myeloid cells influences secondary intention wound healing in mouse skin. In Vivo 23:879-84
Valuckaite, Vesta; Zaborina, Olga; Long, Jason et al. (2009) Oral PEG 15-20 protects the intestine against radiation: role of lipid rafts. Am J Physiol Gastrointest Liver Physiol 297:G1041-52
Ross, Christopher C; MacLeod, Stewart L; Plaxco, Jason R et al. (2008) Inactivation of thrombomodulin by ionizing radiation in a cell-free system: possible implications for radiation responses in vascular endothelium. Radiat Res 169:408-16

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