Exposure to antibiotics during infancy and subsequent risk of Crohn's disease: a

描述（由申请人提供）： 候选人是一名儿科胃肠病学家，在以患者为导向的研究方法方面接受过严格的培训，并致力于将这些方法应用于炎症性肠病（IBD）的研究，包括克罗恩病（CD）和溃疡性结肠炎（UC）。候选人的长期职业目标是成为一名独立资助的医生科学家，结合传统和遗传流行病学方法来确定遗传易感人群中可改变的风险因素。候选人的短期职业目标是1）获得遗传学，遗传流行病学，药物流行病学和研究伦理学的必要背景，以便在儿科IBD中进行基因-环境相互作用的研究，2）发展成功领导多学科研究团队所需的专业技能，以及3）产生临界质量的初步数据和出版物，以作为R 01的PI。拟议的研究计划，职业发展活动，导师团队和机构环境都是唯一适合帮助申请人实现这些目标。我们的总体假设是，CD风险是由以下因素之间的复杂相互作用决定的：1）影响肠道微生物群发育的“早期”暴露，2）可能改变微生物群的“疾病诱发”暴露，3）限制细菌杀灭并允许持续刺激异常免疫反应的易感基因。在本提案中，PI将检验特定假设，即生命早期暴露于抗生素（可能破坏微生物群的发育）是CD的风险因素，特别是在遗传易感个体中。在目标1中，PI将进行一项回顾性出生队列研究，包括1995年至2007年期间在丹麦出生的约900，000名儿童。基于人群的处方登记、患者登记、病理学数据库和丹麦政府维护的其他管理数据将用于测量主要暴露、潜在混杂因素和关注的结局。在目标2中，PI将确定基于人群的病例对照研究的可行性，该研究将传统流行病学方法与额外收集的遗传数据相结合，以评估基因-环境相互作用。为了支持候选人的职业发展，他将在遗传流行病学，药物流行病学，生物统计学和研究伦理学领域进行高级课程和独立研究。导师团队，其中包括国际公认的，独立资助的研究人员在胃肠道流行病学（桑德勒），遗传流行病学（密立根），IBD发病机制（Sartor），流行病学方法（索伦森）和研究伦理（Dressler）的专业知识将指导博士Kappelman的研究和职业发展。研究环境，包括转化和临床科学研究所和胃肠生物学和疾病中心在奥胡斯大学和临床流行病学系将提供一个富有成效的，合议和协作的氛围，在追求上述研究和培训目标。 公共卫生相关性： 近60万美国人受到克罗恩病（CD）的影响，这是一种慢性、特发性、炎症性肠病（IBD），导致大量发病，包括频繁住院和手术、错过工作和学校以及生活质量下降。这项研究和后续研究的目标是确定易感个体中潜在的可改变的风险因素。这可能会导致疾病预防的战略。

DESCRIPTION (provided by applicant): The candidate is a pediatric gastroenterologist with strong training in patient-oriented research methodology, and a proven commitment to applying these methods to the study of the inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC). The candidate's long-term-career goal is to be an independently funded physician scientist, combining both traditional and genetic epidemiological methods to identify modifiable risk factors in genetically susceptible populations. The candidate's short-term career goals are 1) to acquire the necessary background in genetics, genetic epidemiology, pharmacoepidemiology, and research ethics in order to conduct studies of gene-environment interactions in pediatric IBD, 2) to develop the professional skills needed to successfully lead multidisciplinary research teams, and 3) to produce the critical mass of preliminary data and publications to be credible as the PI of an R01. The proposed research plan, career development activities, mentorship team, and institutional environment are all uniquely suited to assist the applicant in achieving these goals. Our overarching hypothesis is that CD risk is determined by complex interactions between 1) "early-life" exposures that impact the development of gut microbiota, 2) "disease-precipitating" exposures that may alter the microbiota, and 3) susceptibility genes which limit bacterial killing and allow persistent stimulation of an abnormal immune response. In this proposal, the PI will test the specific hypothesis that early-life exposure to antibiotics, which may disrupt the development of the microbiota, is a risk factor for CD, particularly in genetically susceptible individuals. In Aim 1, the PI will conduct a retrospective birth cohort study including approximately 900,000 children born in Denmark between 1995 and 2007. Population-based prescription registries, patient registries, pathology databases, and other administrative data maintained by the Danish government will be used to measure the primary exposure, potential confounders, and outcomes of interest. In Aim 2, the PI will establish the feasibility of a population-based case control study that combines traditional epidemiological methods with the additional collection of genetic data in order to assess gene-environment interactions. To support the candidate's career development, he will pursue advanced coursework and independent study in the areas of genetic epidemiology, pharmacoepidemiology, biostatistics, and research ethics. The mentorship team, which includes internationally-recognized, independently-funded investigators with expertise in gastrointestinal epidemiology (Sandler), genetic epidemiology (Millikan), IBD pathogenesis (Sartor), epidemiology methods (Sorensen), and research ethics (Dressler) will guide Dr. Kappelman's research and career development. The research environment including the UNC Translational and Clinical Sciences Institute and Center for Gastrointestinal Biology and Disease at UNC and the Department of Clinical Epidemiology at the University of Aarhus will provide a productive, collegial, and collaborative atmosphere in which to pursue the above research and training goals. PUBLIC HEALTH RELEVANCE: Nearly 600 thousand Americans are affected by Crohn's disease (CD), a chronic, idiopathic, inflammatory bowel disease (IBD) that results in substantial morbidity including frequent hospitalization and surgery, missed work and school, and reductions in quality of life. The goal of this and subsequent research is to identify potentially modifiable risk factors in susceptible individuals. This could lead to strategies for disease prevention.