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

确定基因组和微生物在儿童早期炎症性肠病中的作用

基本信息

批准号：
10408105
负责人：
Maire Abraham Conrad
金额：
$ 18.53万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-16 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408105
关键词：
2 year old 6 year old Achievement Adult Age Child Childhood Chronic Disease Collaborations Complex Coupled Cross-Sectional Studies Data Defect Development Development Plans Diagnosis Disease Disease susceptibility Enrollment Environment Environmental Exposure Environmental Risk Factor Etiology Frequencies Future Genes Genetic Genomics Immune Immune response Immune system Immunologics Incidence Inflammation Inflammatory Bowel Diseases Intestines Lead Life Mentors Morbidity - disease rate Newly Diagnosed Oligogenic Traits Onset of illness Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Population Predisposition Prevalence Process Quality of life Refractory Research Research Personnel Research Proposals Role SNP array Severity of illness Shotguns Structure Susceptibility Gene Technology Time Training Treatment outcome Underserved Population Variant Work age group base biomarker identification career career development conventional therapy disease diagnosis disease phenotype disorder risk early childhood early life exposure early onset exome sequencing gut microbiome gut microbiota illness length improved infancy innovation insight large datasets metagenomic sequencing microbial microbial community microbial signature microbiome microbiota molecular sequence database multidisciplinary novel polygenic risk score rare variant research and development response skills stool sample symposium targeted treatment therapeutic target therapeutically effective therapy design translational study

项目摘要

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.

项目总结/文摘