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

婴儿期接触抗生素以及随后患克罗恩病的风险：

基本信息

批准号：
8460845
负责人：
MICHAEL D KAPPELMAN
金额：
$ 15.17万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-18 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8460845
关键词：
Absenteeism at work Accounting Affect Age Alleles American Animal Model Antibiotics Area Autoimmune Diseases Bacteria Biology Biometry Birth Case-Control Studies Child Childhood Childhood Asthma Chronic Clinical Clinical Sciences Cohort Studies Collection Commit Complex Conflict (Psychology)Crohn&apos s disease DNA Data Databases Denmark Development Digestive System Disorders Disease Disease susceptibility Ensure Environment Environmental Exposure Environmental Risk Factor Epidemiologic Methods Epidemiologic Studies Epidemiology Exposure to Faculty Family Family history of Functional disorder Funding Future Gastroenterologist Gender Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Risk Genetic Variation Genomics Genotype Goals Government Hospitalization Immune Immune Response Genes Immune response Individual Inflammatory Bowel Diseases Inflammatory disease of the intestine Institutes Interdisciplinary Study International Intestines Knowledge Lead Life Mails Measurement Measures Mediating Mentorship Methods Monozygotic Twinning Monozygotic twins Morbidity - disease rate National Institute of Diabetes and Digestive and Kidney Diseases Nested Case-Control Study North Carolina Operative Surgical Procedures Outcome Pathogenesis Pathology Pharmacoepidemiology Physicians Physicians&apos Offices Population Principal Investigator Proxy Public Health Publications Quality of life Recording of previous events Records Registries Relative Risks Research Research Ethics Research Infrastructure Research Methodology Research Personnel Research Training Resources Risk Risk Factors Salivary Sampling Schools Scientist Series Susceptibility Gene Technical Expertise Testing Time Training Translational Research Ulcerative Colitis Universities Venipunctures Virulence Factors Visit Work base career career development clinical epidemiology commensal microbes cost effective design disorder prevention disorder risk early life exposure early onset experience gastrointestinal gene environment interaction genetic epidemiology gut microbiota infancy innovation interest killings member microbial modifiable risk multidisciplinary patient oriented research patient registry planetary Atmosphere population based preclinical study public health relevance receptor research and development skills success

项目摘要

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.

描述（由申请人提供）：该候选人是一名儿科胃肠病医生，在以患者为导向的研究方法方面进行了强有力的培训，并且对将这些方法应用于炎症性肠道疾病（IBD）（包括克罗恩病（CD）（CD）和溃疡性结肠炎（UC））的良好承诺。候选人的长期职业目标是成为一名独立资助的医师科学家，结合了传统和遗传流行病学方法，以鉴定遗传易感人群中的可修改风险因素。候选人的短期职业目标是1）获得遗传学，遗传流行病学，药物学学和研究伦理的必要背景，以进行基因环境相互作用的研究，以开发基因 - 环境相互作用，2）2）2）2）为开发专业技能，以促进多学科研究的专业技能，并以多学科研究为准。 R01。拟议的研究计划，职业发展活动，指导团队和机构环境都非常适合帮助申请人实现这些目标。我们的总体假设是，CD风险取决于1）“早期”暴露之间的复杂相互作用，影响肠道菌群发展的“早期”暴露，2）“疾病至关重要的“暴露”可能会改变微生物群的暴露，3）3）易感基因，这些易感基因限制了细菌杀伤并允许持续刺激异常免疫反应。在该提议中，PI将检验以下特定假设：早期对抗生素的暴露可能破坏微生物群的发展，是CD的危险因素，尤其是在遗传易感的个体中。在AIM 1中，PI将进行回顾性的出生队列研究，其中包括1995年至2007年期间在丹麦出生的约900,000名儿童。基于人群的处方注册机构，患者注册表，病理数据库以及丹麦政府维护的其他行政数据将用于衡量衡量主要暴露者，潜在的混杂因素和感兴趣的结果。在AIM 2中，PI将建立基于人群的案例控制研究的可行性，该研究将传统的流行病学方法与遗传数据的其他收集相结合，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，药物电子学，生物统计学和研究伦理方面进行高级课程和独立研究。该指导团队包括具有胃肠道流行病学专业知识的国际认可，独立资助的研究人员（Sandler），遗传流行病学（Millikan），IBD发病机理（SARTOR）（SARTOR），流行病学方法（Sorensen）和研究伦理学（Dressler）将指导Kappelman博士的研究和研究。 UNC的UNC转化和临床科学研究所以及胃肠道生物学和疾病中心在内的研究环境以及AARHUS大学临床流行病学系的研究环境将提供一种富有成效的，大学和协作的氛围，以追求上述研究和培训目标。