Molecular Pathogenesis of Radiation Enteropathy

腹部放射治疗通常受肠毒性（放射性肠病）风险的剂量限制。 放射性肠病的特征在于上皮屏障破坏、粘膜炎症和进行性纤维化。 肥大细胞增生和纤维化细胞因子的过度表达，最明显的是TGF-β 1，是细胞和分子水平上的突出特征。 PI最近证实肥大细胞和TGF-β 1都参与了肠放射性纤维化的机制，但它们的纤维化作用似乎是相互依赖的;蛋白酶激活受体2（PAR-2），由肥大细胞类胰蛋白酶激活并介导促有丝分裂和纤维化反应，在肠放射性纤维化中上调;并且维持肥大细胞和肠感觉神经之间的正常神经免疫通讯似乎对于适当的辐射应答是关键的。 拟议的研究将使用经验证的转基因动物模型，沿着定量分子方法，系统地剖析肥大细胞通过与TGF-β 1、PAR-2和肠神经的相互作用来调节肠辐射反应的机制。 该项目将1）检查肥大细胞在TGF-β 1激活和稳定中的假定作用; 2）评估肝素在体内作为放射性肠病中重要肥大细胞介导剂的作用; 3）调查PAR-2在肠放射性纤维化机制中的作用; 4）检查肥大细胞在感觉神经消融增强放射性肠病的机制中的作用;和5）评估P物质受体拮抗剂是否调节放射性肠病以及这种作用是否是肥大细胞依赖性的。 这些实验将为肠道辐射反应的基本发病机制提供实质性的新见解。 全面了解这些潜在机制对于确定新的干预目标至关重要。 该项目可能有助于制定具体的策略，以最大限度地减少肠道辐射毒性，从而使放射治疗更安全，更有效。

Abdominal radiation therapy is often dose-limited by the risk of intestinal toxicity (radiation enteropathy). Radiation enteropathy is characterized by epithelial barrier breakdown, mucosal inflammation, and progressive fibrosis. Mast cell hyperplasia and overexpression of fibrogenic cytokines, most notably TGF-beta1, are prominent features at the cellular and molecular levels. The PI recently demonstrated that mast cells and TGF-beta1 are both mechanistically involved in intestinal radiation fibrosis, but their fibrogenic effects appear to be mutually dependent; that protease-activated receptor 2 (PAR-2), which is activated by mast cell tryptase and mediates mitogenic and fibrogenic responses, is upregulated in intestinal radiation fibrosis; and that maintaining normal neuroimmune communication between mast cells and enteric sensory nerves appears to be critical for an appropriate radiation response. The proposed research will use validated, genetically modified animal models, along with quantitative molecular methods, to systematically dissect the mechanisms by which mast cells may modulate the intestinal radiation response through interactions with TGF- beta1, PAR-2, and enteric nerves. The project will 1) examine the putative role of mast cells in TGF-beta1 activation and stabilization; 2) assess, in vivo, the role of heparin as an important mast cell mediator in radiation enteropathy; 3) investigate the role of PAR-2 in the mechanism of intestinal radiation fibrosis; 4) examine the role of mast cells in the mechanisms by which sensory nerve ablation augments radiation enteropathy; and 5) assess whether a substance P receptor antagonist modulates radiation enteropathy and whether this effect is mast cell-dependent. These experiments will provide substantial new insight into the basic pathogenesis of the intestinal radiation response. A comprehensive understanding of these underlying mechanisms is critical for identifying novel targets for intervention. This project may facilitate development of specific strategies to minimize intestinal radiation toxicity, thereby making radiation therapy safer and more effective.