ENDOTHELIAL DYSFUNCTION IN INTESTIAL RADIATION TOXICITY

肠辐射毒性（辐射性肠病）是 其特征在于肠壁的进行性纤维化， 炎症和纤维化细胞因子的过度表达， 转化生长因子B 1（TGF-B 1）。微血管损伤被认为是 在慢性放射性肠病的发病机制中起重要作用。然而，在这方面， 内皮损伤、血管硬化和 延迟辐射毒性尚未在体内确定。临床 PI实验室的实验研究表明， 照射肠中血栓调节蛋白的下调。TM是一种内皮 一种细胞糖蛋白，通过调节凝血酶而起到“天然抗凝剂”的作用 功能凝血酶除了在凝血中起关键作用外， 调节炎症和组织重塑。其中许多功能是 通过蛋白酶激活受体（PAR）介导，最显著的是PAR-1， 在实验性放射性肠病中上调。照射后， TM水平不足增强纤维蛋白沉积并上调TGF-β 1。的 因此，纤维化刺激可以由TGF-β 1与纤维化刺激一起维持。 凝血酶介导的促凝血、促炎症和促有丝分裂作用 通过PAR-1。拟议的研究审查的相对意义 这些过程在放射性肠病的机制。使用体内大鼠 和小鼠模型沿着与定量分子方法，该项目将 系统地研究TM、PAR-1和TGF-β的作用和相互关系 1.该项目将：1）评估 内皮细胞TM、PAR-1、TGF- B 1和结构性肠辐射 损伤，2）使用突变和敲除动物模型来检查特异性 TM、PAR-1和TGF-β 1的相互关系和相对意义， 放射性肠病，和3）测试是否血小板特异性抑制剂 聚集和凝血酶将废除结构，细胞和分子 辐射引起的变化。这些实验将提供重要的新 关于慢性化的分子发病机理和机制的信息 放射性肠病全面了解这些潜在的 机制可以识别临床相关的干预目标， 促进制定治疗和预防策略， 肠辐射毒性

Intestinal radiation toxicity (radiation enteropathy) is characterized by progressive fibrosis of the intestinal wall and over-expression of inflammatory and fibrogenic cytokines, particularly transforming growth factor b 1 (TGF-b 1). Microvascular injury is believed to be important in the mechanisms of chronic radiation enteropathy. However, direct molecular links among endothelial injury, vascular sclerosis, and delayed radiation toxicity have not been established in vivo. Clinical experimental studies from the PI's laboratory have shown a striking down-regulation of thrombomodulin in irradiated intestine. TM is an endothelial cell glycoprotein that acts as a "natural anticoagulant" by regulating thrombin function. Thrombin, in addition to its key role in coagulation, is an important regulator of inflammation and tissue remodeling. Many of these functions are mediated through protease activated receptors (PAR), most notably PAR-1, which is upregulated in experimental radiation enteropathy. After irradiation, deficient levels of TM enhance fibrin deposition and upregulate TGF-b 1. The fibrotic stimulus may thus be sustained by TGF-b 1 in concert with procoagulant, pro-inflammatory, and mitogenic effects of thrombin, mediated through PAR-1. The proposed research examines the relative significance of these processes in the mechanisms of radiation enteropathy. Using in vivo rat and mouse models along with quantitative molecular methods, the project will systematically examine the roles and interrelationships of TM, PAR-1, and TGF-b 1. The project will 1) assess temporal and spatial associations among endothelial cell TM, PAR-1, TGF- b 1, and structural intestinal radiation injury, 2) use mutant and knockout animal models to examine specific interrelationships and the relative significance of TM, PAR-1, and TGF-b 1 in radiation enteropathy, and 3) test whether specific inhibitors of platelet aggregation and thrombin will abrogate the structural, cellular, and molecular changes induced by radiation. These experiments will provide significant new information regarding the molecular pathogenesis and mechanisms of chronicity of radiation enteropathy. A comprehensive understanding of these underlying mechanisms may identify clinically relevant targets for intervention and facilitate development of therapeutic and prophylactic strategies to minimize intestinal radiation toxicity.