Mount Sinai NYC Genetics Research Center: Multi-omic integration across data-types, cell niches and populations

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PROJECT ABSTRACT This proposal is submitted in response to FOA RFA-DK-21-022, to serve as a Genetics Research Center (GRC), within the NIDDK Inflammatory Bowel Disease (IBD) Genetics Consortium (IBDGC), at the Icahn School of Medicine at Mount Sinai, New York. During the present period, we made substantive progress in defining mechanisms of anti-TNF non-response in ileal Crohn’s disease and defined the role of NOD2 mutations in altering blood monocyte differentiation to result in an aberrant myeloid-stromal niche. In this proposal, we seek to expand on the role of blood monocyte differentiation, but newly-focused on perianal fistulae, a major unmet medical need in Crohn’s disease, disproportionately affecting African-Americans. Single cell transcriptomics has provided enormous insight into molecular mechanisms in IBD; our lab has substantial expertise in this and will leverage new approaches including multiome ATAC + transcriptome and higher resolution spatial transcriptomics platforms available soon. Aim 1 will focus on direct ex-vivo single cell analyses involving perianal fistulae including African-American and European ancestry Crohn’s disease patients. Aim 2 will expand in vitro analyses focusing on rectal-derived enteroids and serial blood leukocyte and platelet analyses. Both epithelial cells and monocytes can differentiate into mesenchymal-type cells. The extent to which stem- and other pluripotent cells are imprinted with chronic inflammation and during acute flares vs. remission will be evaluated via multiome ATAC + transcriptome and serial blood leukocyte and platelet analyses. Comparative analyses of these multi-omic data across European vs. African-American cohorts focused on GWAS loci will be performed, focusing on WNT, AP-1 and reactive oxygen species’ effects. Iterating between direct ex-vivo data (Aim 1) and in vitro systems (Aim 2) will provide maximal insight. Aim 3 describes our proposed contributions to the IBDGC broadly. We have been major contributors to Consortium-wide clinical recruitment efforts (ileal resection, ulcerative colitis demarcation), and more recently, recruitment of African-American and Hispanic IBD patients. We have reported on the particular value of African-American case-control reference data for both common (improving polygenic risk scores) and rare (overlap with very-early onset IBD genes) genetic variants. Beyond perianal Crohn’s disease, new recruitment of ulcerative colitis patients hospitalized with acute flares is proposed; serial blood analyses are feasible, with key short-term outcomes. A complete explication of mechanisms underlying IBD locus associations will require deeper genomic interrogation across populations, as well as data integration across space (cellular niches, disease extent), key clinical scenarios and time.