Montreal-Boston Collaborative GRC

项目摘要 炎症性肠病（IBD）的特征在于肠粘膜的慢性复发性炎症。 胃肠道克罗恩病（CD）（MIM 266600）和UC（MIM 191390）是克罗恩病的两种主要亚型。 IBD。NIDDK炎症性肠病遗传学联盟（IBDGC）成立于2002年7月， 目的是鉴定易患IBD的遗传变异。波士顿协作IBD 遗传研究中心（GRC）是IBDGC的创始成员。在目前的提案中，我们有三个 具体目标： SA #1：表征目前人群中IBD表型的遗传结构 在IBD基因组研究中的代表性不足。目的：利用地方血统分解， 鉴定在美国混合样本中独特富集的变异，以确定以前被忽视的遗传风险因素 在西班牙裔和非洲裔美国人中，IBD的发病率更高。 SA#2：利用纵向多组学方法揭示临床疾病的生物学原因 IBD的异质性和不同的治疗反应。目的：招募和前瞻性 在开始分子靶向治疗后随访IBD患者。我们将生成和/或分析 遗传学、血清代谢组学和血液单细胞RNA测序数据和测试基线样本 （在开始治疗前即刻）和首次临床评估时采集的样品。患者将 跟踪了一年。 SA#3：新鉴定的CD基因PDLIM 5及其剪接区变体的分析及其影响 对上皮功能的影响目的：确定一个新发现的CD基因的功能，并将其定位于 在其他IBD基因的生物学背景下，使用患者来源的材料、类器官和基于hiPSC的 模型 我们致力于在我们的遗传和功能研究中包括两性，包括性别作为一个变量， 我们的数据收集、结果分析和结果报告。这包括源自患者的细胞模型 (e.g. hiPSC衍生系）。我们还将确保在不同的遗传背景下进行实验 并确定这是否影响测定和/或模型的扰动效应或基线行为。

PROJECT ABSTRACT The inflammatory bowel diseases (IBD) are characterized by chronic relapsing inflammation of the gastrointestinal tract. Crohn's disease (CD) (MIM 266600) and UC (MIM 191390) are the two main subtypes of IBD. The NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC) was established in July 2002 for the purpose of identifying genetic variation predisposing to IBD. The Montreal-Boston Collaborative IBD Genetic Research Center (GRC), is a founding member of the IBDGC. In the current proposal we have three Specific Aims: SA#1: To characterize the genetic architecture of IBD phenotypes within populations currently underrepresented in IBD genomic research. OBJECTIVE: To employ local ancestry decomposition to identify variants uniquely enriched in US admixed samples to identify previously overlooked genetic risk factors contributing more substantially to IBD in Hispanic and African-American populations. SA#2: To exploit longitudinal multi `omic approaches to reveal the biological causes of the clinical heterogeneity of IBD and differential treatment response. OBJECTIVE: To recruit and prospectively follow IBD patients following the initiation of molecularly-targeted therapies. We will generate and/or analyze genetic, serum metabolomics, and blood single-cell RNA-sequencing data and test baseline samples (immediately prior to initiation of therapy) and samples taken at first clinical assessment. Patients will be followed for a period of one year. SA#3: Analysis of the newly identified CD gene PDLIM5 and its splice region variant and their impact on epithelial functions. OBJECTIVE: To determine the function of a newly identified CD gene and placing it in the biological context of other IBD genes using patient-derived materials, organoids and hiPSC-based models. We are committed to including both sexes in our genetic and functional studies, including sex as a variable in our data collection, analysis of results, and reporting of findings. This includes patient-derived cellular models (e.g. hiPSC-derived lines). We will also ensure that the experiments are done on diverse genetic backgrounds and determine if this impacts the effect of perturbation or baseline behavior of the assay and/or model.