An in depth study of mast cell tryptase as a novel mediator in colitis

描述(由申请人提供)：尽管我们对炎症性肠病(IBD)病因的了解最近取得了重大进展，但我们的知识存在空白，某些患者的治疗选择可能有限。肥大细胞是一种位于肠道中的效应性免疫细胞，在先天免疫中起着重要作用。尽管它被认为是重要的，因为它在肠道组织的炎症部分出现的增加，它的作用在很大程度上是未知的。我已经确定，一种从激活的肥大细胞释放的介质，小鼠肥大细胞蛋白-6(mMCP-6)，在化学诱导的小鼠结肠炎中起着重要的促炎作用。人类与mMCP-6的同源基因是类胰蛋白酶-1，它是人类中占主导地位的肥大细胞类胰蛋白酶。根据我们小组发表的研究和我的初步数据，我假设mMCP-6作用于改变上皮屏障的通透性，并将中性粒细胞带到炎症部位。我将使用我们在各种结肠炎模型中创建的缺乏mMCP-6的小鼠品系，使用培养的肥大细胞和上皮细胞以及重组鼠和人肥大细胞类胰蛋白酶进行体外研究，以广泛研究肥大细胞类胰蛋白酶在结肠炎中的作用机制。我也是 将测试一种mMCP-6的抑制剂，该抑制剂可能对IBD患者具有未来的治疗意义。我将在一个机构中进行这些研究，在那里我可以获得各种资源，包括设施、导师、合作者和顾问。在这种环境下，在我的导师和合作者的指导下，我将准备实现我成为一名独立调查员的目标。

DESCRIPTION (provided by applicant): Although there have been significant recent gains into our understanding of what causes Inflammatory Bowel Disease (IBD), there are voids in our knowledge and treatment options may be limited for certain patients. The mast cell is an effector immune cell that resides in the intestine and plays an important role in innate immunity. Although it has been thought to be important based on its increased presence in inflamed segments of intestinal tissue, its role is largely unknown. I have determined that a mediator released from activated mast cells, mouse mast cell protease-6 (mMCP- 6), plays an essential pro-inflammatory role in chemically-induced colitis in mice. The human ortholog to mMCP-6 is Tryptase-¿1 which is the dominant mast cell tryptase in humans. Based on published studies from our group and my preliminary data, I hypothesize that mMCP-6 acts to alter the permeability of the epithelial barrier and to bring neutrophils to the site of inflammation. I willuse strains of mice we have created to lack expression of mMCP-6 in various colitis models, in vitro studies using cultured mast cells and epithelial cells, and recombinant mouse and human mast cell tryptase to extensively study the mechanism of action of mast cell tryptase in colitis. I also will test an inhibitor of mMCP-6 which may have future therapeutic significance for patients with IBD. I will perform these studies in an Institution where every resource is available to me including facilities, mentors, collaborators, and advisers. In this environment and with the guidance of my mentors and collaborators, I will be poised to attain my goal of becoming an independent investigator.