Oral elafin formulation for intestinal fibrosis

项目摘要 长期的克罗恩病会导致肠纤维化，这是很难预防或治疗的。外科手术 切除手术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 受到积极追捧。我们最近发现，肠道抗菌肽和抗菌素的表达 蛋白酶抑制剂elafin在狭窄的CD患者中减少。其对肠道的潜在保护作用 纤维化在文献中从未被报道过。我们的初步数据显示，弹力纤维- 过表达抑制TNBS介导的沙门氏菌感染的小鼠先前存在的结肠纤维化 小鼠，SAMP1/YitFc小鼠。我们产生了一种口服活性弹力纤维-欧德拉吉配方 治疗应用。Elafin-Eudradit制剂逆转了先前存在的结肠纤维化 经TNBS处理的小鼠。我们还发现，弹力芬抑制了肠道中胶原的表达。 通过调节几个狭窄特异基因对成纤维细胞的影响。我们假设口服给药 改良的弹力纤维可能有助于通过影响狭窄来治疗结肠炎相关性肠纤维化- 特定的路径。我们建议(1)建立改良弹力纤维的口服治疗方案 肠纤维化的小鼠模型和(2)组织蛋白酶S的测定 PAR2-miR205-ZEB1介导的Elafin在肠成纤维细胞中的抗纤维化机制。整体而言 这项研究的影响将产生对优化口服弹力芬给药的全面评估 肠纤维化的治疗方法。这项机制研究将揭示伊拉芬是如何以及为什么抑制 肠道纤维化。

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.