Anti-inflammatory Role of Mast Cell-Derived Bone Morphogenetic Proteins in Inflammatory Bowel Disease

项目摘要 炎症性肠病（IBD）是一种慢性、复发性疾病，无法治愈。IBD是一项治疗挑战 由于对治疗缺乏反应，以及药物的副作用，包括继发性感染， 恶性肿瘤风险增加。此外，许多IBD患者发展为肠纤维化， 有效的药物治疗。当纤维化发生时，患者接受腹部手术进行肠切除。一 一种既抗炎又抗纤维化的医学方法在这些疾病中是非常有价值的。 病人，但目前还没有。 我们以前的研究表明，肥大细胞是控制IBD炎症的关键因素。在 特别地，肥大细胞在慢性结肠炎中具有抗炎功能，即使它们是促炎性的 急性结肠炎基于高通量筛选，我们将骨形态发生蛋白（BMP）鉴定为 肥大细胞保护作用的候选分子。BMP是抗炎细胞因子， 具有抗纤维化的特性。我们已经证明肥大细胞在慢性而非急性时产生BMP， 用炎症介质刺激。 我们的假设是肥大细胞衍生的BMP是抑制炎症的关键抗炎因子， 预防纤维化，促进IBD的愈合。在强有力的初步数据的指导下，本提案的目的是 1）确定BMP是否是结肠炎中肥大细胞抗炎作用的关键介质，和2） 确定BMP在限制纤维化和促进慢性IBD愈合中的作用。 我们期望该项目的成功完成将证明肥大细胞衍生的BMPs作为 肠道中的关键抗炎、抗纤维化和促愈合介质。BMP已经可用 治疗上，但使用受到短半衰期的限制，因此需要高剂量来实现 持续效果。这些实验应该会导致针对BMP通路的替代方法， 希望能发现引起持续的内源性BMP上调的方法， IBD患者的肠道。乐观地说，这些结果可能导致开发有效的抗- 炎症和抗纤维化药物。这些发现也可以外推到其他慢性 炎症性疾病，如哮喘。

PROJECT SUMMARY Inflammatory bowel disease (IBD) is a chronic, relapsing condition with no cure. IBD is a therapeutic challenge due to lack of response to therapy, and side effects of medications including secondary infections and increased risk of malignancy. Furthermore, many IBD patients develop intestinal fibrosis, for which there is no effective medical therapy. When fibrosis occurs, patients undergo abdominal surgery for bowel resection. A medical approach that was both anti-inflammatory and anti-fibrotic would be extremely valuable in these patients, but is not currently available. Our previous studies have demonstrated that mast cells are key players controlling inflammation in IBD. In particular, mast cells have anti-inflammatory functions in chronic colitis even though they are proinflammatory in acute colitis. Based on high-throughput screens, we identified bone morphogenetic proteins (BMPs) as candidate molecules for the protective effect of mast cells. BMPs are anti-inflammatory cytokines that also have anti-fibrotic properties. We have demonstrated that mast cells produce BMPs upon chronic, but not acute, stimulation with inflammatory mediators. Our hypothesis is that mast cell-derived BMPs are critical anti-inflammatory factors that dampen inflammation, prevent fibrosis, and promote healing in IBD. Guided by strong preliminary data, the aims of this proposal are to 1) determine if BMPs are critical mediators of the anti-inflammatory effects of mast cells in colitis and 2) determine the role of BMPs in limiting fibrosis and promoting healing in chronic IBD. We expect that successful completion of this project will demonstrate the role of mast cell-derived BMPs as key anti-inflammatory, anti-fibrotic, and pro-healing mediators in the intestine. BMPs are already available therapeutically, but use has been limited by the short half-life and resultant high doses needed to achieve sustained effect. These experiments should lead to alternative approaches to target the BMP pathway, hopefully leading to the discovery of methods to cause sustained endogenous BMP upregulation in the intestine of patients with IBD. Optimistically, these results could lead to development of effective anti- inflammatory and anti-fibrotic medications. These findings may also be extrapolated to other chronic inflammatory conditions such as asthma.