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

项目总结/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由于其独特的严重发病率表型、对常规治疗反应差、持续时间长 疾病，以及其迅速增长的流行。该人群进一步分为诊断<2年的人群 年龄，婴儿IBD和2至6岁之间诊断的儿童，我们称之为幼儿期 IBD对于这个建议。虽然小儿IBD是一种复杂的多基因疾病，我们和其他人已经确定了致病因素， 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IBD这一建议的基本假设是，儿童早期IBD患者具有独特的 宿主基因组背景加上早期生活暴露。这种互动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联系。PI将利用这一职业 发展和研究计划，以获得技能，并建立合作，这将使她发展 利用大数据集的未来转化研究，以确定未来的治疗靶点，从而改善治疗 早期儿童IBD的结局。 利用尖端技术，我们将生成基因组和微生物组数据，以研究儿童早期 儿童IBD在目标1中，PI将使用全外显子组鉴定罕见和低频变异的作用。 基于已知的IBD易感性基因座测序并计算多基因风险评分，以表征 早期儿童IBD表型的遗传负担。在目标2中，粪便样本将在 在100例新诊断的早期儿童IBD患者中开始IBD治疗的前8周， 收集有关环境暴露的数据。霰弹枪宏基因组测序将用于辨别 每个时间点的微生物群落结构。基线微生物群将与早期生活相关 环境暴露和纵向微生物群将在不断变化的疾病背景下进行分析 活动作为其职业发展计划的一部分，该研究计划允许PI完善和获得技能 在导师的支持下，接受合作者的实践培训，参加正式的课程， 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.