"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.

 描述（由申请人提供）：肠易激综合症 (IBS) 是一种慢性胃肠道 (GI) 疾病，影响约 15% 的美国人口，导致 360 万人次就诊，每年造成约 200 亿美元的医疗保健费用。引起 IBS 的病理生理机制仍知之甚少，感染后 IBS (PI-IBS) 是 IBS 的一个子集，其特征是急性发作后出现症状。据估计，3% 至 36% 的胃肠炎患者会患上 PI-IBS。感染性胃肠炎在美国很常见（每年 4800 万例）；然而，对于 PI-IBS 的发病机制了解有限。我对研究空肠弯曲菌感染后的 PI-IBS 感兴趣，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变化，通过与我为此提案建立的明尼苏达州卫生部 (MDH) 的合作，将确定急性空肠弯曲菌肠炎病例。我强有力的初步数据表明，在明尼苏达州的人中，空肠弯曲菌肠炎后 PI-IBS 很常见（22%），并且体内和离体结肠粘膜屏障功能受损。 PI-IBS。我的初步数据还表明，导致 PI-IBS 的空肠弯曲菌菌株比对照菌株（未导致 PI-IBS）对体外屏障功能造成更大的破坏。我还发现粪便微生物根据这些初步数据，空肠弯曲菌 PI-IBS 患者的群落多样性降低，我的总体假设是空肠弯曲菌通过引起菌株和宿主依赖性的屏障功能改变而导致 PI-IBS。我将在 3 个具体目标中检验这一假设，我将通过 MDH 和梅奥医学实验室鉴定培养阳性的空肠弯曲菌肠炎酶。在具体目标 1 中，我将评估结肠上皮的结构和功能。急性空肠弯曲菌肠炎患者的屏障功能，并在 6 个月时跟踪患者以确定 PI-IBS 的发展，然后我将评估 PI-IBS 患者和对照（感染但未感染）的屏障功能。在具体目标 2 中，我将研究 PI-IBS 和对照空肠弯曲菌菌株对屏障功能的影响，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，我将确定急性衣原体感染期间是否存在微生物群特征。空肠弯曲菌肠炎有助于预测 PI-IBS 的发展 该提案将独特地允许使用体内和离体综合技术对来自美国社区的样本中确认的空肠弯曲菌感染后的 PI-IBS 发展机制进行研究。识别发生 PI-IBS 的“高风险”肠炎病例，并制定预防或治疗 PI-IBS 的未来干预措施 我的 K23 长期目标是指导以患者为导向的研究生涯。开发奖的目的是成为一名独立研究者，参与确定 IBS 机制的转化研究。从拟议研究中获得的实验结果和机制信息将为 R03 和 R01 应用奠定基础并生成初步数据。将参与许多职业发展和培训活动。这些活动将集中于粘膜屏障功能的测量、分子生物学、空肠弯曲菌基因组学、宿主微生物群测序和生物信息学。此外，我还将参加相关的教学。课程作业、参加研讨会和全国会议并进行演讲，以收集反馈并扩大该领域未来转化工作的合作。这一时期将包括由 NIH 资助的国际知名博士 Michael Camilleri 和 Gianrico Farrugia 博士提供的结构化导师指导。梅奥诊所的研究环境包括临床和转化科学中心、细胞信号传导中心。胃肠病学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、团结和协作的氛围，以开展拟议的研究和培训活动。在本次职业发展奖结束时，我将成为一名独立的人。领导多学科转化研究团队的医师科学家。