Endothelial Dysfunction in Intestinal Radiation Toxicity

描述（由申请人提供）：腹部放射治疗通常受到肠毒性（放射性肠病）风险的剂量限制。放射性肠病的特征在于上皮屏障破坏和粘膜炎症，以及随后进行性纤维化和血管硬化的发展。微血管损伤被认为是促进放射性肠病的发展，但分子联系尚未在体内建立。PI进行的临床和临床前研究强烈表明，辐射诱导的内皮功能障碍，特别是由于血栓调节蛋白（TM）表达缺陷导致的血管血栓阻力丧失，在机制上参与了辐射性肠病的发生。TM是调节凝血酶功能的内皮细胞蛋白，并且基本上将凝血酶从促凝血剂转化为抗凝剂。照射后，TM水平不足导致凝血酶形成增加。凝血酶除了在凝血中起关键作用外，还调节炎症和纤维化。本研究项目使用经验证的转基因动物模型和药物化合物，沿着定量分子方法，在体内系统地检查a）凝血酶在肠道辐射反应背景下的各种作用的相对重要性，和B）旨在改善放射性肠病的内皮定向干预。具体而言，该项目将1）检查纤维蛋白沉积是否对肠放射性纤维化产生不利影响; 2）研究阻断细胞凝血酶受体（蛋白酶激活受体1）是否改善放射性肠病; 3）评估外源性给予活化蛋白C（一种在TM存在下由凝血酶激活的抗凝剂和抗炎介质）是否影响肠放射反应; 4）测试他汀类药物（一种常用的具有血管保护作用的降胆固醇药物）是否改善慢性肠辐射纤维化;和5）确定他汀类药物的肠保护作用是否需要TM的上调。这些研究将为肠道辐射反应的基本发病机制提供实质性的新见解。全面了解这些潜在机制对于确定临床相关的干预目标至关重要。因此，该项目可能有助于制定具体的策略，以尽量减少肠道辐射毒性，从而使放射治疗更安全，更有效。

DESCRIPTION (provided by applicant): 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.