Endothelial Dysfunction in Intestinal Radiation Toxicity

说明(申请人提供)：腹部放射治疗通常受到肠道毒性(放射性肠病)风险的剂量限制。放射性肠病的特征是上皮屏障破坏和粘膜炎症，随后发展为进行性纤维化和血管硬化。微血管损伤被认为促进放射性肠病的发展，但在体内尚未建立分子联系。PI进行的临床和临床前研究有力地表明，放射性导致的内皮功能障碍，特别是由于血栓调节蛋白(TM)表达不足而导致的血管血栓抵抗力丧失，在机制上参与了放射性肠病的发展。TM是一种内皮细胞蛋白，调节凝血酶的功能，本质上将凝血酶从促凝剂转变为抗凝血剂。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。这项研究项目使用经过验证的转基因动物模型和药理化合物，以及定量分子方法，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，以及b)旨在改善放射性肠病的内皮导向干预。具体地说，该项目将1)检查纤维蛋白沉积是否对肠道辐射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是否可改善放射性肠病；3)评估外源性给予活化蛋白C是否影响肠道辐射反应；4)测试他汀类药物是否可改善慢性肠道辐射纤维化；5)确定他汀类药物的肠道保护作用是否需要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。对这些潜在机制的全面了解对于确定临床相关的干预靶点至关重要。因此，该项目可以促进制定具体的战略，将肠道辐射毒性降至最低，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.