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. ? ?
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