肠纤维化是导致克罗恩病（CD）肠道并发症发生和患者接受手术治疗主要的原因，目前缺乏有效治疗手段。炎症是肠纤维化的启动因素，但单纯控制炎症并不能阻止纤维化进展。我们前期发现1.CD特征性的病理改变--肠系膜脂肪增生与肠固有肌增生程度相关；2.增生的肠系膜脂肪分泌游离脂肪酸（FFA）水平明显升高，且能通过激活脂肪酸氧化（FAO）通路促进肠固有肌层平滑肌细胞（HIMC）增殖；3.肠纤维化部位肉毒碱棕榈酰转移酶-1（CPT-1）活性上调，而拮抗CPT-1可抑制HIMC增殖。由此我们提出科学假设：肠系膜脂肪分泌的FFA经由CPT-1进入 HIMC线粒体内，激活FAO通路影响线粒体功能，促进HIMC增殖，从而介导肠纤维化形成。本项目拟使用人体肠系膜脂肪组织、肠道原代细胞及CPT-1基因敲除小鼠，阐明CD增生的肠系膜脂肪通过影响细胞能量代谢促进肠纤维化形成的分子机制，有望为CD肠纤维化的治疗提供新靶点。

Intestinal stricture induced by fibrosis is the commonest factor leading to bowel complications and subsequent surgery. Inflammation is the initiation factor for fibrosis, but targeting inflammation merely could not prevent the progression of intestinal fibrosis. As a hallmark of Crohn’s disease (CD), creeping fat is highly associated with fibrosis, but how creeping fat contributes to intestinal fibrosis remains unclear. Our preliminary result showed creeping fat secretes higher amounts of free fatty acid (FFA) which significantly induces proliferation of human muscularis propria smooth muscle cell (HIMC). CPT-1 (carnitine palmitoyltransferase 1) is the key regulatory enzyme of mitochondrial FFA oxidation related to cell proliferation. We have previously demonstrated that CPT-1 activity is upregulated in intestinal fibrosis from CD patients, and inhibiting CPT-1 could abrogate the proliferation of HIMC induced by FFA. The hypothesis of this project is that creeping fat derived FFA increase FFA oxidation in mitochondria through CPT-1, which contributes to the proliferation of HIMC and intestinal fibrosis. This project aims to explore, in a unique mechanism, the role of creeping fat in pathogenesis of intestinal fibrosis, and focuses on FFA oxidation, mitochondrial function and cell metabolism using primary human mesenteric fat t issue, primary human intestinal cells and CPT-1 knock out mice model. As such, the anticipated results will bring us closer to understand the novel fundamental mechanisms driving this intestinal fibrosis and may provide insight on potential target for treating intestinal fibrosis.