Using molecular quantitative trait loci mapping approaches to determine candidate gene regulatory mechanisms of functional variants within inflammatory bowel disease GWAS loci.

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Nina  Nishiyama
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $42,574
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

1 PROJECT SUMMARY/ABSTRACT
 2
 3 Inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis are chronic inflammatory
 4 disorders that cause damage to the gastrointestinal tract. There is no cure for IBD. Current therapies treat
5 inflammatory responses but do not target underlying causes. Research improving our understanding of
 6 underlying causes of IBD can lead to improved treatment of disease. The intestinal epithelial barrier plays a
 7 critical role in the development of chronic intestinal inflammation. There is increasing evidence that barrier
 8 function and immune responses in IBD are influenced by genetic factors and confer disease risk. While over 200
 9 genomic loci have been associated with IBD by genome-wide association studies (GWAS), only a handful of
10 these loci have known molecular mechanisms. Loci falling within non-coding regions suggests variants perturb
11 regulatory mechanisms by altering transcription factor binding and local chromatin structure but identifying exact
12 mechanisms and target genes remains challenging using GWAS alone. Mapping molecular quantitative trait loci
13 associate traits such as gene expression (eQTL) and chromatin accessibility (caQTL) with genetic variants,
14 provides evidence to functionally link variants to regulatory mechanisms and target genes. Mapping QTL in
15 diseased tissue specifically will identify regulatory mechanisms active in disease. I hypothesize that using a
16 QTL approach in colonic mucosa can reveal functional IBD variants and their regulatory mechanisms that may
17 be altered in the presence of disease. In Aim 1 I will map eQTL in IBD colon tissue to identify putative target
18 genes of IBD GWAS loci. In Aim 2 I will map caQTL in colon tissue to identify functional variants within regulatory
19 elements that may modulate expression of target genes by altering binding of transcription factors. In Aim 3 I will
20 determine the functional consequences of altered expression of CAMK2A, a putative IBD GWAS target gene,
21 on intestinal epithelial barrier function. Together, these aims will increase our understanding of the molecular
22 pathogenesis of IBD by uncovering previously unidentified regulatory mechanisms and target genes of IBD-
23 associated variants and provide novel biomarkers or candidates for therapeutic targets. This proposal seeks to
24 leverage the rigorous coursework, computational resources, collaborative environment, curated mentorship, and
25 access to clinical samples available at the University of North Carolina at Chapel Hill to provide the best possible
26 Ph.D. training in Bioinformatics and Computational Biology. This project will not only elucidate the functional role
27 of variants contributing to the molecular pathophysiology of IBD but will also provide the valuable experience
28 and training necessary for a career as an independent research investigator.

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