MOLECULAR PATHOGENESIS OF RADIATION ENTEROPATHY

描述：(改编自申请人的摘要)：腹部放射 治疗往往受到肠道毒性(辐射)风险的剂量限制 肠病)。放射性肠病与持续和 持续的转化生长因子-b在以下区域的过度表达 显示结构性损伤。这个项目检验了1)转化生长因子-b的假设 过度表达是放射性肠病的独立预测因子，2) 辐射后转化生长因子-β水平的调节对慢性前列腺炎发生的影响 辐射损伤及并发症，3)转化生长因子-β发挥更大的作用 在继发性放射性肠病(慢性损伤)中的重要作用 继发于粘膜破坏)而不是原发放射性肠病 (慢性损伤，无粘膜破坏)，以及4)之间的相互作用 肥大细胞和转化生长因子-β在慢性肾小球疾病发病机制中起重要作用。一个循环 小鼠的小肠通过外科手术附着在雄性大鼠的阴囊中。这个 肠道中的“阴囊疝气”随后被照射，产生 肠道并发症和形态损害与所见相似 从临床上看。转化生长因子-β的表达与组织病理学、细胞学、形态计量学 并对照射后26周内的功能变化进行评估。 具体目标是：1)评估转化生长因子-β 肠道的表达、辐射剂量、观察时间和参数 毒性，2)确定在损伤急性期是否添加转化生长因子-β 增加后续放射性肠病的严重程度，3)确定 创伤急性期应用转化生长因子-β的中和改善作用 随后的慢性放射性肠病，4)比较转化生长因子-β在 继发性与原发性放射性肠病，以及5)评估转化生长因子-b 肥大细胞缺陷大鼠放射性肠病的表达及严重程度 与有肥大细胞能力的小蜂窝相比。来自这些的结果 实验将提供有关分子的重要新信息。 放射性肠病的发病机制。更好地理解这些 机制将促进治疗方案和 将肠道毒性降至最低的干预措施，因此有可能 提高鼻咽癌患者的放射治疗比例 腹部肿瘤。

DESCRIPTION: (Adapted from the applicant's abstract): Abdominal radiation therapy is often dose-limited by the risk of intestinal toxicity (radiation enteropathy). Radiation enteropathy is associated with consistent and sustained transforming growth factor b (TGF-b) overexpression in areas that display structural injury. This project tests the hypotheses that 1) TGF-b overexpression is an independent predictor of radiation enteropathy, 2) Modulation of post-radiation TGF-b levels affects development of chronic radiation-induced lesions and complications, 3) TGF-b plays a more significant role in consequential radiation enteropathy (chronic injury secondary to mucosal break-down) than in primary radiation enteropathy (chronic injury without mucosal disruption), and 4) interactions between mast cells and TGF-b are important in the mechanism of chronicity. A loop of small bowel is surgically attached in the scrotum of male rats. The intestine in the "scrotal hernia" is subsequently irradiated, producing intestinal complications and morphologic lesions similar to those seen clinically. TGF-b expression and histopathologic, cellular, morphometric, and functional changes are assessed up to 26 weeks after irradiation. Specific aims are to 1) assess quantitative associations between TGF-b expression, radiation dose, observation time, and parameters of intestinal toxicity, 2) determine if adding TGF-b during the acute phase of injury increases the severity of subsequent radiation enteropathy, 3) determine if neutralization of TGF-b during the acute phase of injury ameliorates subsequent chronic radiation enteropathy, 4) compare TGF-b expression in consequential versus primary radiation enteropathy, and 5) assess TGF-b expression and severity of radiation enteropathy in mast cell-deficient rats compared to mast cell-competent litter-mates. Results from these experiments will provide significant new information regarding the molecular pathogenesis of radiation enteropathy. An improved understanding of these mechanisms will facilitate development of treatment protocols and interventions to minimize intestinal toxicity, and thus has potential to improve the therapeutic ratio of radiation therapy in patients with abdominal tumors.