Montreal-Boston Collaborative GRC

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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.