Oral elafin formulation for intestinal fibrosis

项目摘要 克罗恩病的长期发展导致肠纤维化，这是难以预防或治疗的。 切除可能会对患者的生活质量产生负面影响。因此，新的治疗方法是 积极追求。我们最近表明，肠道表达的抗菌肽和 蛋白酶抑制剂弹性蛋白酶在狭窄的CD患者中减少。其在肠道中的潜在保护作用 纤维化在文献中从未报道过。我们的初步数据显示弹性蛋白酶- 过表达抑制TNBS介导的小鼠、沙门氏菌感染的小鼠和未感染的小鼠中预先存在的结肠纤维化。 小鼠和SAMP 1/YitFc小鼠。我们制备了一种口服活性弹性蛋白-Eudragit制剂， 治疗应用。弹性蛋白-Eudragit制剂逆转了结肠癌患者先前存在的结肠纤维化。 TNBS处理的小鼠。我们还发现，弹力蛋白抑制胶原蛋白的表达在肠道 成纤维细胞通过调节几个狭窄特异性基因。我们假设口服 修饰的弹力素可用于治疗结肠炎相关的肠纤维化， 具体途径。我们建议（1）建立口服修饰的弹力素治疗方案， 在预先存在的肠纤维化的小鼠模型中测定肠纤维化和（2）测定组织蛋白酶S- PAR 2-miR 205-ZEB 1介导的肠成纤维细胞中弹性蛋白酶的抗纤维化机制。整体 这项研究的影响将产生一个全面的评估优化口服弹力素输送 肠纤维化的治疗方法这项机制研究将揭示如何以及为什么弹性蛋白抑制 肠纤维化

Project Summary Prolonged Crohn’s disease leads to intestinal fibrosis, which is difficult to prevent or treat. The surgical resection may negatively impact a patient’s quality of life. Thus, new therapeutic approaches are actively sought after. We have recently shown that intestinal expression of antimicrobial peptide and protease inhibitor elafin is reduced in stricturing CD patients. Its potential protective effect in intestinal fibrosis has never been reported in the literature. Our preliminary data showed that elafin- overexpression inhibited preexisting colonic fibrosis in TNBS-mediated mice, Salmonella-infected mice, and SAMP1/YitFc mice. We generated an orally active elafin-Eudragit formulation for potential therapeutic applications. The elafin-Eudragit formulation reversed preexisting colonic fibrosis in TNBS-treated mice. We also discovered that elafin inhibits collagen expression in the intestinal fibroblasts by modulating several stricture-specific genes. We hypothesize that oral administration of modified elafin may be useful for treating colitis-associated intestinal fibrosis by affecting a stricture- specific pathway. We propose to (1) establish oral therapeutic regimens of modified elafin for treating intestinal fibrosis in a mouse model of preexisting intestinal fibrosis and (2) determine the cathepsin S- PAR2-miR205-ZEB1-mediated anti-fibrogenic mechanism of elafin in intestinal fibroblasts. The overall impact of this study will produce a comprehensive assessment of optimized oral elafin delivery approaches for intestinal fibrosis. This mechanistic study will reveal how and why elafin inhibits intestinal fibrosis.