MOLECULAR PATHOGENESIS OF RADIATION ENTEROPATHY

描述：（改编自申请人摘要）：腹部放射 治疗通常受到肠毒性（辐射）风险的剂量限制 肠病）。 放射性肠病与持续性 持续的转化生长因子B（TGF-B）过度表达的区域， 显示结构性损伤。 本项目检验以下假设：1）TGF-β 过度表达是放射性肠病的独立预测因子，2） 辐射后TGF-β水平的调节影响慢性胰腺炎的发展 3）TGF-β在放射性损伤和并发症中起着更重要的作用， 在继发性放射性肠病（慢性损伤 继发于粘膜破坏）比原发性放射性肠病 （慢性损伤，无粘膜破坏），以及4） 肥大细胞和TGF-β在慢性化的机制中是重要的。 环路 小肠的一部分通过手术连接在雄性大鼠的阴囊中。 的 "阴囊疝"中的肠随后被照射， 肠道并发症和形态学病变与所见相似 临床上 TGF-β表达和组织病理学，细胞，形态学， 并在照射后26周评估功能变化。 具体目标是：1）评估TGF-b与 表达、辐射剂量、观察时间和肠参数 毒性，2）确定是否在损伤的急性期加入TGF-β 增加后续放射性肠病的严重程度，3）确定是否 在损伤的急性期中和TGF-β， 随后慢性放射性肠病，4）比较TGF-b表达， 继发性与原发性放射性肠病，以及5）评估TGF-β 肥大细胞缺陷大鼠放射性肠病的表达及严重程度 与肥大细胞活性的同窝仔相比。 从这些 实验将提供重要的新信息， 放射性肠病的发病机制。 更好地理解这些 机制将促进制定治疗方案， 干预措施，以尽量减少肠道毒性，因此有可能 提高放射治疗的有效率 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.