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

描述（由申请人提供）：虽然我们最近对炎症性肠病（IBD）的病因有了很大的了解，但我们的知识存在空白，某些患者的治疗选择可能有限。肥大细胞是存在于肠道中的效应免疫细胞，在先天免疫中起重要作用。虽然它被认为是重要的基础上，它的存在增加发炎段肠组织，其作用在很大程度上是未知的。我已经确定，从活化的肥大细胞释放的介质，小鼠肥大细胞蛋白酶-6（mMCP- 6），在小鼠化学诱导的结肠炎中起着重要的促炎作用。mMCP-6的人类直系同源物是类胰蛋白酶-1，其是人类中主要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的作用是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建立的缺乏mMCP-6表达的小鼠品系，使用培养的肥大细胞和上皮细胞以及重组小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 将测试mMCP-6的抑制剂，其可能对IBD患者具有未来的治疗意义。 我将在一个机构进行这些研究，其中每一个资源都提供给我，包括设施，导师，合作者和顾问。在这样的环境中，在我的导师和合作者的指导下，我将准备好实现我成为一名独立调查员的目标。 肥大细胞在过敏中很重要，但它们对保护我们免受感染也很重要。肥大细胞可以释放一种叫做类胰蛋白酶的物质，我发现这种物质会使某些结肠炎小鼠模型的炎症恶化。我提出了一项深入的研究，看看肥大细胞类胰蛋白酶是如何工作的，这将导致对炎症性肠病患者炎症驱动因素的新理解。此外，我将测试一种药物，旨在阻止肥大细胞类胰蛋白酶的作用，并可能提供一种新的治疗选择来治疗结肠炎。

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. PUBLIC HEALTH RELEVANCE: Mast cells are important in allergy but they are also important to protect us from infections. Mast cells can release a substance called tryptase that I have found makes inflammation worse in certain mouse models of colitis. I propose an in depth study to see how mast cell tryptase works which will lead to new understanding for what drives inflammation in patients with Inflammatory Bowel Disease. Furthermore, I will test a drug that is designed to block the effects of mast cell tryptase and could provide a novel treatment option to treat colitis.