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

肥大细胞类胰蛋白酶作为结肠炎新型介质的深入研究

• 批准号: 8445257
• 负责人: Matthew J Hamilton
• 金额: $ 15.72万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445257
• 关键词: 16p13.3; APC-2059; Abbreviations; Acute; Address; Affect; Anaphylaxis; Antigens; Area; Atherosclerosis; Bacterial Infections; Bacterial Typing; Bone Marrow; Boston; Cells; Chronic; Chymase; Citrobacter rodentium; Clinical; Colitis; Colon; Complement; Crohn' s disease; Data; Digestive System Disorders; Disease; Environment; Epithelial; Epithelial Cells; Etiology; Experimental Arthritis; Fluorescein; Fluorescein-5-isothiocyanate; Fostering; Future; Gastroenterology; Generations; Genes; Goals; Helminths; Hospitals; Human; Human Chromosomes; Hypersensitivity; Immune; Immune response; In Vitro; Inbreeding; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Institution; Interleukins; Intestines; Isothiocyanates; Kininogenase; Klebsiella pneumonia bacterium; Knowledge; Lead; Lung; Matrix Metalloproteinases; Mediator of activation protein; Mentors; Mesylates; Modeling; Molecular; Mouse Strains; Mucositis; Mus; Natural Immunity; Orthologous Gene; Pathogenesis; Patients; Pediatric Hospitals; Peptide Hydrolases; Permeability; Pharmaceutical Preparations; Phase II Clinical Trials; Play; Polymerase Chain Reaction; Publishing; Rattus; Recombinants; Relative (related person); Research Personnel; Resistance; Resources; Role; Serine Protease; Site; Sodium Dextran Sulfate; Sulfonic Acids; System; Testing; Therapeutic; Tissues; Trinitrobenzenes; Tryptase; Ulcerative Colitis; United States; Viral; Woman; Work; base; combat; commensal microbes; design; homologous recombination; human mast cell tryptase; immunoglobulin receptor; improved; in vitro Model; in vivo; inhibitor/antagonist; mast cell; mast cell protease 6; medical schools; mouse model; neutrophil; novel; pathogen

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.

描述（由申请人提供）：尽管最近我们对炎症性肠病（IBD）病因的了解取得了显着进展，但我们的知识仍存在空白，并且对于某些患者的治疗选择可能有限。肥大细胞是一种效应免疫。存在于肠道中并在先天免疫中发挥重要作用的细胞，尽管由于其在肠道组织发炎部分中的存在增加而被认为很重要，但其作用在很大程度上尚不清楚，我已确定释放了一种介质。小鼠肥大细胞蛋白酶 6 (mMCP-6) 来自激活的肥大细胞，在化学诱导的小鼠结肠炎中发挥重要的促炎作用，mMCP-6 的人类直系同源物是类胰蛋白酶-¿ 1 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，我勇敢地说 mMCP-6 可以改变上皮屏障的通透性，并将中性粒细胞带到我将使用的炎症部位。我们建立了在各种结肠炎模型中缺乏mMCP-6表达的小鼠品系，利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，主要研究其机制肥大细胞类胰蛋白酶在结肠炎中的作用我也。 我将测试一种 mMCP-6 抑制剂，该抑制剂可能对 IBD 患者具有未来的治疗意义。在我的导师和合作者的指导下，我将准备好实现成为一名独立调查员的目标。