ENDOTHELIAL DYSFUNCTION IN INTESTIAL RADIATION TOXICITY

肠道辐射毒性(放射性肠病)是 以肠壁进行性纤维化和 炎性和纤维化细胞因子的过度表达，尤其是 转化生长因子β1(TGF-β1)。微血管损伤被认为是 在慢性放射性肠病的发病机制中具有重要作用。然而， 血管内皮细胞损伤、血管硬化症和 延迟性辐射毒性在体内尚未确定。临床 来自PI实验室的实验研究表明， 照射后肠道中血栓调节蛋白的下调。TM是一种内皮细胞 通过调节凝血酶起“天然抗凝剂”作用的细胞糖蛋白 功能。凝血酶除了在凝血中起关键作用外，还是一种重要的 炎症和组织重塑的调节剂。这些函数中有许多是 通过蛋白酶激活的受体(PAR)介导，最著名的是PAR-1，它 在实验性放射性肠病中表达上调。照射后， TM水平不足可促进纤维蛋白沉积和上调转化生长因子-β1。 因此，纤维化刺激可能由转化生长因子-β1与 凝血酶的促凝血、促炎和促有丝分裂作用 通过标准杆1。这项拟议的研究考察了以下因素的相对重要性 这些过程在放射性肠病的发病机制中起重要作用。使用在体大鼠 和老鼠模型以及定量分子方法，该项目将 系统研究TM、PAR-1和转化生长因子-β的作用和相互关系 1.该项目将1)评估 内皮细胞TM、PAR-1、转化生长因子-β1与肠道结构性辐射 损伤，2)使用突变和基因敲除动物模型来检查特定的 结肠癌中TM、PAR-1和TGF-β1的相互关系及相对意义 放射性肠病，以及3)检测是否有特定的血小板抑制物 聚集和凝血酶将破坏结构、细胞和分子。 辐射引起的变化。这些实验将提供重要的新的 慢性疾病分子发病机制的研究进展 放射性肠病。全面了解这些潜在的 机制可以确定临床上相关的干预靶点和 促进制定治疗和预防战略，以尽量减少 肠道辐射毒性。

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.