ENDOTHELIAL DYSFUNCTION IN INTESTIAL RADIATION TOXICITY

肠内辐射毒性中的内皮功能障碍

• 批准号: 6514214
• 负责人: Martin Hauer-Jensen
• 金额: $ 27.14万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514214
• 关键词: genetically modified animals; intestine disorder; laboratory mouse; platelet aggregation inhibitors; radiation dosage; radiation sensitivity; thrombin receptor; thrombomodulin; transforming growth factors; vascular endothelium

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.

肠辐射毒性（辐射肠病）为 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）。微血管损伤被认为是 在慢性辐射肠病的机制中很重要。然而， 内皮损伤，血管硬化和 尚未在体内建立延迟的辐射毒性。临床 PI实验室的实验研究显示出惊人的 辐照肠道中血小板蛋白的下调。 TM是内皮 通过调节凝血酶来充当“天然抗凝剂”的细胞糖蛋白 功能。凝血酶除了其在凝结中的关键作用外，还很重要 炎症和组织重塑的调节剂。这些功能中有许多是 通过蛋白酶活化受体（PAR）介导，最著名的是PAR-1， 在实验辐射肠病中被上调。辐照后， 缺乏TM水平可增强纤维蛋白沉积并上调TGF-B 1。 因此，纤维化刺激可能会与TGF-B 1一起与 凝血酶的促凝剂，促炎和有丝分裂作用 通过par-1。拟议的研究研究了 这些过程中的辐射肠病机理。使用体内大鼠 和鼠标模型以及定量分子方法，该项目将 系统地检查TM，PAR-1和TGF-B的角色和相互关系 1。项目将1）评估时间和空间关联 内皮细胞TM，PAR-1，TGF-B 1和结构肠辐射 伤害，2）使用突变体和敲除动物模型检查特定 相互关系以及TM，PAR-1和TGF-B 1的相对意义 辐射肠病和3）测试是否特定的血小板抑制剂 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 有关分子发病机理和慢性机制的信息 辐射肠病。对这些基础的全面理解 机制可能会确定干预与临床相关的目标和 促进制定治疗和预防性策略，以最大程度地减少 肠辐射毒性。