This proposal is submitted in response to RFA-DK-16-510, ?Limited Competition for the Data Coordinating Center (DCC) for the NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC) (U24)?. IBD affects 1.8 to 3 million Americans; better therapies and more rational use of multiple emerging therapies are urgently needed. Over 200 loci have been associated to IBD, prioritizing cells, genes and pathways that drive pathogenesis. The IBDGC, comprised of the DCC and six Genetic Research Centers (GRCs) throughout North America brings together large IBD referral centers to perform well-powered genetic, expression and functional studies. Novel protocols for intestinal sampling and longitudinal follow-up are needed to define precise cellular and molecular mechanisms.
In Aim 1, the DCC will apply new laboratory and computing technologies to collect accurate, detailed data on disease pathogenesis from the clinic all the way down to the cellular level, and to integrate these data with both existing and new genomic data for sharing with the research community. Platforms for longitudinal collections, integration with top collaborating laboratories, and development of new objective assessments of disease activity and responses to treatment are described. The Bionimbus Protected Data Cloud will facilitate collaborative analyses, and data sharing will be enhanced through an IBD Data Commons.
In Aim 2, prioritization of scientific directions and incorporation of new technologies, sampling strategies and analyses is proposed. Key factors include efficiently scaling processes across centers, minimizing and defining analytic and other sources of variation, and longitudinal analyses. Enhancement of credible SNP set definitions will be achieved through increasing power through increased sample sizes of genome-wide association study SNP sets, combining analyses across inflammatory diseases, and integrating more diverse populations. Comprehensive expression analyses of a spheroid collection of inflamed and uninflamed samples derived from ulcerative colitis (UC) patients will define mRNA expression variation driven by genetic variability, thereby defining drivers of UC pathogenesis. Finally, in a large cohort of Crohn's disease patients undergoing ileal resectional surgery, the genetic basis for how pathophysiologic mechanisms function over time will be defined. This large sample set will enable the examination of genetic variation in response to therapeutic interventions and over time. The long-term goal of these studies is to efficiently develop approaches to most effectively treat IBD patients, catalyzing the advent of Precision IBD.
The primary purpose and scientific mission of the NIDDK IBDGC is to identify the causal genes and genetic variants within the known susceptibility loci and to elucidate the roles of risk-associated genetic variants in the pathophysiology of IBD. Essential scientific elements required to fulfill this purpose include large, diverse sample sizes, engagement of new technologies and collaborators and robust computing platforms to facilitate collaboration and data sharing.
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