Identifying Genomic and Microbial Contributions in Early Childhood-Inflammatory Bowel Disease

项目摘要/摘要 6岁以前诊断的炎症性肠病可以与年龄较大的儿童和 成人IBD以其独特的表型发病严重，对常规治疗反应差，病程较长 疾病的数量及其迅速增加的流行率。这一群体被进一步划分为确诊2岁的人群。 年龄，婴儿IBD，以及被诊断为2至6岁的儿童，我们称之为早期儿童 IBD支持这项提议。虽然儿童IBD是一种复杂的多基因疾病，但我们和其他人已经确定了病因 婴儿IBD的单基因缺陷。然而，对早期的致病机制知之甚少。 儿童炎症性肠病。这一建议的基本假设是，早期儿童IBD患者有独特的 宿主基因组背景与早期生命暴露相结合。这种相互作用导致了一种功能失调的动态 免疫反应和肠道微生物群落结构之间的关系。私家侦探将利用这一职业 制定开发和研究计划，以便获得技能并建立合作关系，使她能够 未来的转化性研究利用大型数据集来确定未来的治疗目标，以改善治疗 儿童早期结局--IBD。 使用尖端技术，我们将产生基因组和微生物组数据来研究早期儿童 儿童炎症性肠病。在目标1中，PI将使用整个外显子组来识别稀有和低频变体的作用 根据已知的IBD易感基因座对多基因风险得分进行测序和计算，以便表征 儿童早期IBD表型的遗传负担。在目标2中，大便样本将在 100例新诊断的儿童早期IBD患者开始IBD治疗的前8周 收集有关环境暴露的数据。鸟枪式元基因组测序将用于识别 每个时间点的微生物群落结构。基线微生物区系将与早期生命相关 环境暴露和纵向微生物区系将在变化的疾病的背景下进行分析 活动。作为她职业发展计划的一部分，这项研究计划允许PI改进和获得技能 在导师的支持下，接受合作者的动手培训，参加正式的课程学习， 并参加多学科研讨会和会议，为她未来的职业生涯做好准备 独立调查员。

Project Summary/Abstract Inflammatory bowel disease diagnosed before age 6 years can be distinguished from older onset pediatric and adult IBD by its unique phenotype of severe morbidity, poor response to conventional therapies, greater duration of disease, and its rapidly increasing prevalence. This population is further divided into those diagnosed <2 year of age, infantile IBD, and children diagnosed between 2 and 6 years old, whom we refer to as early childhood IBD for this proposal. While pediatric IBD is a complex polygenic disease, we and others have identified causative monogenic defects in infantile IBD. However, little is understood about the pathogenic mechanisms in early childhood IBD. The underlying hypothesis of this proposal is that patients with early childhood IBD have a unique host genomic background coupled with early life exposures. This interaction leads to a dysfunctional dynamic between the immune response and the intestinal microbial community structure. The PI will utilize this career development and research plan in order to gain skills and establish collaborations which will allow her to develop future translational studies leveraging large data sets to identify future therapeutic targets to improve treatment outcomes for early childhood-IBD. Using cutting edge technology, we will generate genomic and microbiome data to study children with early childhood IBD. In Aim 1, the PI will identify the role of both rare and low frequency variants using whole exome sequencing and calculate the polygenic risk score based on known IBD susceptibility loci in order to characterize the genetic burden of the early childhood IBD phenotype. In Aim 2, stool samples will be collected during the first 8 weeks of initiating IBD treatment in 100 newly diagnosed early childhood IBD patients in addition to collecting data regarding environmental exposures. Shotgun metagenomic sequencing will be used to discern the microbial community structure at each time point. The baseline microbiota will be correlated with early life environmental exposures and the longitudinal microbiota will be analyzed in the context of changing disease activity. As part of her career development plan, this research plan with allow the PI to refine and acquire skills with the support of her mentors, receive hands on training from her collaborators, enroll in formal coursework, and participate in multidisciplinary seminars and conferences to prepare her for a future career as an independent investigator.