ENDOTHELIAL DYSFUNCTION IN INTESTIAL RADIATION TOXICITY

肠道放射毒性（放射性肠病）是 以肠壁进行性纤维化为特征 炎症和纤维化细胞因子的过度表达，特别是 转化生长因子 b 1 (TGF-b 1)。据认为，微血管损伤 在慢性放射性肠病的机制中很重要。然而， 内皮损伤、血管硬化之间的直接分子联系 体内延迟辐射毒性尚未确定。临床 PI 实验室的实验研究表明， 受辐射肠道中血栓调节蛋白的下调。 TM是一种内皮细胞 通过调节凝血酶充当“天然抗凝剂”的细胞糖蛋白 功能。凝血酶除了在凝血中发挥关键作用外，还是一种重要的 炎症和组织重塑的调节剂。其中许多功能是 通过蛋白酶激活受体 (PAR) 介导，尤其是 PAR-1， 在实验性放射性肠病中上调。照射后， TM 水平不足会增强纤维蛋白沉积并上调 TGF-b 1。 因此，纤维化刺激可能由 TGF-b 1 协同维持 凝血酶介导的促凝血、促炎和促有丝分裂作用 通过 PAR-1。拟议的研究探讨了以下方面的相对意义： 放射性肠病机制中的这些过程。使用大鼠体内 和小鼠模型以及定量分子方法，该项目将 系统地研究 TM、PAR-1 和 TGF-b 的作用和相互关系 1. 该项目将 1) 评估之间的时间和空间关联 内皮细胞 TM、PAR-1、TGF-b 1 和结构性肠道放射 损伤，2）使用突变和敲除动物模型来检查特定的 TM、PAR-1 和 TGF-b 1 的相互关系和相对重要性 放射性肠病，3) 测试是否有血小板特异性抑制剂 聚集和凝血酶将消除结构、细胞和分子 辐射引起的变化。这些实验将提供重要的新 有关慢性病的分子发病机制和机制的信息 放射性肠病。全面了解这些底层 机制可以确定临床相关的干预目标 促进治疗和预防策略的制定，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.