Microbiota in Intestinal Fibrosis

肠道纤维化中的微生物群

基本信息

批准号：
9330151
负责人：
Florian Rieder
金额：
$ 15.52万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-28 至 2021-09-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330151
关键词：
Address Animal Model Apoptosis CASP1 gene Cells Clinic Clinical Collagen Complex Crohn&apos s disease Data Disease Dissection Effector Cell Environment Environmental Risk Factor Extracellular Matrix FRAP1 gene Fibronectins Fibrosis Flagellin Genes Genetic Transcription Germ-Free Goals Health Human Immune Immune response Immunosuppressive Agents In Vitro Inflammasome Inflammatory Bowel Diseases Interleukins International Intestinal Fibrosis Intestinal Obstruction Intestines Knowledge Laboratories Lead Link Mediating Mentors Mesenchymal Microbiology Muscle Cells Myelogenous Myofibroblast Operative Surgical Procedures Organ Pathway interactions Patient Care Patients Pattern recognition receptor Peptide Initiation Factors Phosphatidylinositols Phosphotransferases Post-Transcriptional Regulation Prevention Preventive Program Development Proteins Regulation Reporting Research Research Institute Resolution Role Scientific Advances and Accomplishments Signal Pathway Signal Transduction Sirolimus Structure System TLR5 gene Testing Therapeutic Therapeutic Agents Time Toll-like receptors Transgenic Animals Transgenic Mice Translation Initiation Translational Regulation Treatment Efficacy Ulcerative Colitis Work career career development cell type disabling symptom experience experimental study fibrogenesis gain of function gut microbiota human tissue in vivo innovation loss of function microbial microbiota mouse model novel novel strategies novel therapeutics programs receptor research and development response statistics tissue culture transcriptomics translational approach

项目摘要

PROJECT SUMMARY This project proposes a comprehensive five-year mentored research development program with transition to independence. The research plan investigates the severe clinical problem of intestinal fibrosis and stricture formation in inflammatory bowel diseases (IBD). It explores the entirely novel concept of a direct effect of bacterial components on intestinal mesenchymal cells, the chief pro-fibrotic cell type, in vitro and in vivo. We found that human intestinal myofibroblasts respond to activation of bacterial sensing pattern recognition receptors, but only flagellin increases secretion of the extracellular matrix (ECM) components fibronectin and collagen 1. This response is post-transcriptionally regulated and dependent on caspase 1, implicating the inflammasome in intestinal fibrosis. Therefore, we propose to explore the following hypothesis: the gut microbiota induces intestinal fibrosis through a flagellin mediated pathway. This hypothesis will be tested through three interrelated, but indepedent specific aims: (1) to define the mechanisms of flagellin- induced post-transcriptional regulation of ECM secretion in vitro (2) to determine the role of flagellin mediated inflammasome activation in the pro-fibrogenic responses in primary human mesenchymal cells in vitro and (3) to explore the effect of abrogating flagellin signaling in experimental fibrosis in vivo during induction and resolution of intestinal fibrosis. Post-transcriptional regulation and inflammasome activation via caspase 1 are two entirely original mechanisms of intestinal fibrosis. We will use a cutting edge transgenic mouse model that allows control of the timing of deletion of bacterial sensing in vivo specifically in mesenchymal cells. This enables exploration of microbial sensing in the prevention and resolution of intestinal fibrosis. The research will be carried out in the laboratory of Dr. Fiocchi MD, Lerner Research Institute (LRI), Cleveland Clinic, and will be advised by a panel of international experts in human and experimental fibrogenesis, translational regulation and the microbiota. The advisory panel has worked out a structured career development program, including formal coursework in microbiology, translational regulation and statistics. An ideal intellectual and technical environment is in place locally in the LRI. My career goal is to build and lead an independent research program that will advance scientific knowledge and patient care in the field of intestinal fibrosis. My prior experience with primary human cell systems and animal models gives me the ideal basis to be a successful K08 awardee. The proposed study will provide novel evidence for the direct effect of the microbiota in intestinal mesenchymal cell induced fibrogenesis and stricture formation. These findings could lead to a completely novel approach of targeting the microbiota as a therapeutic strategy to abrogate fibrosis.

项目概要该项目提出了一个为期五年的全面指导研究开发计划，并过渡到独立。该研究计划调查肠道纤维化和狭窄的严重临床问题炎症性肠病（IBD）的形成。它探索了直接影响的全新概念肠道间充质细胞（主要的促纤维化细胞类型）上的细菌成分在体外和体内。我们发现人类肠道肌成纤维细胞对细菌传感模式识别的激活做出反应受体，但只有鞭毛蛋白会增加细胞外基质 (ECM) 成分纤连蛋白和胶原蛋白 1。这种反应是转录后调节的并且依赖于 caspase 1，这意味着肠纤维化中的炎症小体。因此，我们建议探索以下假设：肠道微生物群通过鞭毛蛋白介导的途径诱导肠道纤维化。这个假设将是通过三个相互关联但独立的具体目标进行测试：（1）定义鞭毛蛋白的机制体外诱导 ECM 分泌转录后调节 (2) 确定鞭毛蛋白的作用原代人间充质细胞促纤维化反应中介导的炎症小体激活体外细胞和（3）探索废除鞭毛蛋白信号传导对实验性纤维化的影响体内肠道纤维化的诱导和消退过程中。转录后调控和通过 caspase 1 激活炎症小体是肠道纤维化的两种完全原始的机制。我们将使用一个最先进的转基因小鼠模型，可以控制体内细菌传感删除的时间特别是在间充质细胞中。这使得探索微生物传感在预防和治疗中的应用成为可能。肠道纤维化的解决。该研究将在 Fiocchi MD, Lerner 博士的实验室进行克利夫兰诊所研究所 (LRI)，并将由人类和人类健康领域的国际专家小组提供建议实验纤维发生、翻译调节和微生物群。顾问小组制定了一个结构化的职业发展计划，包括微生物学、转化监管的正式课程和统计数据。 LRI 当地拥有理想的知识和技术环境。我的职业目标是建立并领导一个独立的研究计划，该计划将促进科学知识和患者护理肠道纤维化领域。我之前在原代人类细胞系统和动物模型方面的经验让我成为成功的 K08 获奖者的理想基础。拟议的研究将为直接的研究提供新的证据微生物群对肠道间充质细胞诱导纤维发生和狭窄形成的影响。这些研究结果可能会带来一种全新的方法，以微生物群为目标，作为治疗策略消除纤维化。