"Barrier function alterations in post-infectious irritable bowel syndrome"

“感染后肠易激综合征的屏障功能改变”

• 批准号: 9306841
• 负责人: Madhusudan Grover
• 金额: $ 16.74万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-03 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306841
• 关键词: Acute; Address; Affect; American; Animal Model; Area; Bacteria; Bioinformatics; Campylobacter; Campylobacter jejuni; Center for Translational Science Activities; Chronic; Clinic; Clinical Sciences; Collaborations; Communities; Coupled; Data; Development; Diarrhea; Disease; Environment; Epithelial; Etiology; Feedback; Foundations; Functional disorder; Funding; Future; Gastroenteritis; Gastroenterology; Gastrointestinal Diseases; Gastrointestinal tract structure; Genes; Genomics; Goals; Health; Health Care Costs; Impairment; In Vitro; Incidence; Individual; Infection; Inflammation; International; Intervention; Intestines; Irritable Bowel Syndrome; K-Series Research Career Programs; Laboratories; Lead; Measurement; Mediating; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Minnesota; Molecular Biology; Myosin Light Chain Kinase; Myosin Light Chains; Nonmuscle Myosin Type IIA; Pathway interactions; Patients; Permeability; Phosphorylation; Physicians; Population; Positioning Attribute; Proteins; Public Health; Recruitment Activity; Research; Research Activity; Research Personnel; Resistance; Risk; Role; Sampling; Scientist; Signal Transduction; Structure; Symptoms; Techniques; Testing; Tight Junctions; Training; Training Activity; Translational Research; United States National Institutes of Health; Virulence; Visit; Work; base; career development; cohort; educational atmosphere; enteritis; experimental study; gastrointestinal infection; genome sequencing; healthy volunteer; high risk; improved; in vivo; individualized medicine; insight; interest; meetings; microbial; microbial community; microbiota; motility disorder; multidisciplinary; novel; pathogen; patient population; patient subsets; persistent symptom; prevent; professional atmosphere; prospective; public health relevance; therapy development; translational study; whole genome

 DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder that affects approximately 15% of the U.S. population, generates 3.6 million physician visits, and accounts for an estimated $20 billion in health care costs annually. The pathophysiological mechanisms responsible for IBS remain poorly understood. Post- infectious IBS (PI-IBS) is a subset of IBS characterized by development of symptoms following an episode of acute gastroenteritis. It has been estimated that 3 to 36% of people who suffer from gastroenteritis develop PI- IBS. Infectious gastroenteritis is common in the U.S. (48 million cases annually); however, there is limited mechanistic insight into development of PI-IBS. I am interested in studying PI-IBS following infection with Campylobacter jejuni, a leading cause bacterial enteritis in the U.S. and a reportable illness to the public health departments. I will study the pathophysiological mechanisms of PI-IBS with a focus on intestinal barrier function and microbiota changes. Through collaboration with the Minnesota Department of Health (MDH) that I established for this proposal, acute C. jejuni enteritis cases will be identified and recruied. My strong preliminary data suggest that PI-IBS is common (22%) following C. jejuni enteritis in people from Minnesota, and in vivo and ex vivo colonic mucosal barrier function is impaired in PI-IBS. My preliminary data also suggests that C. jejuni strains that lead to PI-IBS cause greater disruption of in vitro barrier function than the control strains (that did not lead to PI-IBS). Additionally, I found that fecal microbial community diversity is decreased in C. jejuni PI-IBS patients. Based on these preliminary data, my overall hypothesis is that C. jejuni leads to PI-IBS by causing a strain and host-dependent alteration in barrier function and microbiota changes. I will test this hypothesis in 3 specific aims. I will identify culture-positive C. jejuni enteritis ases through the MDH and the Mayo Medical Laboratory. In specific aim 1, I will assess the structure and function of the colonic epithelial barrier in acute C. jejuni enteritis patients and follow thee patients at 6 months to ascertain PI-IBS development. I will then assess barrier function in PI-IBS patients and controls (infection but no subsequent development of PI-IBS). In specific aim 2, I will study effects of PI-IBS and control C. jejuni strains on barrier function, especially delineating the role of myosin light chain phosphorylation in barrier function and determine genomic differences among strains using whole genome sequencing. In specific aim 3, I will study the role of fecal and mucosal microbiota changes in development of PI-IBS. I will determine if there are microbiota signatures during acute C. jejuni enteritis that help predict development of PI-IBS. This proposal will uniquely allow the study of mechanisms for PI-IBS development following confirmed C. jejuni infection in samples derived from the U.S. communities using integrative in vivo and ex vivo techniques with the aim of identifying "high-risk" enteritis cases for development of PI-IBS and developing strategies for future interventions to prevent or treat PI-IBS. My long-term goal with a K23 mentored patient-oriented research career development award is to become an independent investigator involved in translational studies determining mechanisms of IBS. The experimental results and mechanistic information gained from the proposed study will form the foundation for and generate preliminary data for R03 and R01 applications. Over the next five years, I will be involved in a number of career development and training activities. These will be focused around the measurement of mucosal barrier function, molecular biology, C. jejuni genomics, host microbiota sequencing and bioinformatics. Additionally, I will take relevant didactic coursework, attend and present at seminars and national meetings to gather feedback and expand collaborations for future translational work in the area. This period will involve structured mentoring from Dr. Michael Camilleri and Dr. Gianrico Farrugia, both internationally-renowned, NIH-funded investigators in areas of research in neurogastroenterology and motility disorders with an exceptional track record of mentoring. The research environment at Mayo Clinic, including the Center for Clinical and Translational Science, the Center for Cell Signaling in Gastroenterology and the Center for Individualized Medicine together with my collaboration with MDH, provides me a productive, collegial, and collaborative atmosphere to pursue the proposed research and training activities. At the conclusion of this career development award, I will be positioned to be an independent physician-scientist leading a multidisciplinary translational research team.

 肠易激综合征（IBS）是一种慢性胃肠道（GI）疾病，影响约15%的美国人口，每年有360万人次就诊，估计每年的医疗保健费用为200亿美元。肠易激综合征的病理生理机制仍然知之甚少。感染后IBS（PI-IBS）是IBS的一个亚组，其特征在于急性胃肠炎发作后出现症状。据估计，3%至36%的患有胃肠炎的人发展成PI-IBS。感染性胃肠炎在美国很常见（每年4800万例）;然而，对PI-IBS发展的机制了解有限。我有兴趣研究感染空肠弯曲菌后的PI-IBS，空肠弯曲菌是美国细菌性肠炎的主要原因，也是公共卫生部门应报告的疾病。我将研究PI-IBS的病理生理机制，重点是肠道屏障功能和微生物群的变化。通过与明尼苏达州卫生部（MDH）的合作，我建立了这个建议，急性C。并会收集有关空肠肠炎的个案。我强有力的初步数据表明，PI-IBS是常见的（22%），其次是C。来自明尼苏达州的人的空肠肠炎，并且在PI-IBS中体内和离体结肠粘膜屏障功能受损。我的初步数据还表明，C。导致PI-IBS的空肠菌株比对照菌株（不会导致PI-IBS）对体外屏障功能造成更大的破坏。另外，我发现C.空肠PI-IBS患者。基于这些初步数据，我的总体假设是C。空肠炎通过引起屏障功能和微生物群变化的菌株和宿主依赖性改变而导致PI-IBS。我将在三个具体目标中检验这个假设。我会鉴定出培养阳性的C通过MDH和马约医学实验室进行空肠肠炎试验。在具体目标1中，我将评估急性丙型肝炎中结肠上皮屏障的结构和功能。空肠肠炎患者，并在6个月时随访三名患者，以确定PI-IBS的发展。然后，我将评估PI-IBS患者和对照组（感染但随后未发生PI-IBS）的屏障功能。在具体目标2中，我将研究PI-IBS和对照C的作用。空肠菌株的屏障功能，特别是描绘肌球蛋白轻链磷酸化在屏障功能中的作用，并使用全基因组测序确定菌株之间的基因组差异。在具体目标3中，我将研究粪便和粘膜微生物群变化在PI-IBS发展中的作用。我将确定急性C型肝炎时是否有微生物群特征。空肠肠炎有助于预测PI-IBS发展。这一建议将独特地允许在确认C.使用体内和离体综合技术，在来自美国社区的样品中检测空肠感染，目的是鉴定PI-IBS发展的“高风险”肠炎病例，并制定未来干预措施以预防或治疗PI-IBS的策略。我的长期目标是获得K23指导的以患者为导向的研究职业发展奖，成为一名独立的研究人员，参与确定IBS机制的转化研究。从拟议的研究中获得的实验结果和机理信息将为R 03和R 01应用奠定基础并产生初步数据。在接下来的五年里，我将参与一些职业发展和培训活动。这些将集中在粘膜屏障功能的测量，分子生物学，C。空肠基因组学、宿主微生物群测序和生物信息学。此外，我将采取相关的教学课程，出席并出席研讨会和国家会议，以收集反馈意见，并扩大合作，为该地区未来的翻译工作。这一时期将涉及Michael Camilleri博士和Gianrico Farrugia博士的结构化指导，他们都是国际知名的NIH资助的神经胃肠病学和动力障碍研究领域的研究人员，具有出色的指导记录。马约诊所的研究环境，包括临床和转化科学中心、胃肠病学细胞信号中心和个体化医学中心，以及我与MDH的合作，为我提供了一个富有成效、学院式和协作的氛围，以追求拟议的研究和培训活动。在这个职业发展奖的结论，我将被定位为一个独立的医生，科学家领导一个多学科的转化研究团队。