# Functional Molecular Investigation of Inflammatory Bowel Disease (IBD) Risk Variants

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $161,500

## Abstract

PROJECT SUMMARY/ ABSTRACT
Inflammatory bowel disease (IBD) is a chronic disease characterized by intermittent 
episodes of intestinal inflammation and disruption of the intestinal epithelial barrier. The 
 IBD Genetics Consortium has intensively studied the genetic architecture of this complex disease. 
Assigning molecular mechanisms to IBD risk variants is critical to understanding disease 
etiology and identify new drug targets. Human genetics has potential to provide an unbiased view 
of the causative disease mechanisms. IBD already has been the subject of intensive genetic 
investigations, including genome-wide association studies (GWAS) that have uncovered dozens of risk 
loci. However, mechanistic understanding of these risk loci has been a challenge because the vast 
majority falls outside of genes, in non-coding regions of the genome. In contrast to 
protein-coding regions of the genome where we understand the amino acid code, we still do not 
have a clear framework to understand how non-coding genome variants alter cell function and 
contribute to disease. To learn how DNA variation throughout the genome affects cellular 
pathways and contributes to IBD, we now need a deeper understanding of the function of non-coding 
genome elements in the specific cell types that drive the pathology.

We propose targeted CRISPR-based genome perturbations in primary human T cells, human 
intestinal organoids (HIOs) and in vivo murine models of IBD pathology to characterize 
both critical cis-regulatory elements and functional pathways that are affected by IBD 
risk variants. Genome perturbations in primary immune cells, HIOs and murine models will 
 identify target genes regulated by these critical non-coding elements and identify the 
cell-type or stimulation-specific conditions where IBD risk variants impair gene 
regulation. We will assess how non-coding variation at sites implicated by human 
genetics alters gene regulatory programs in inflammatory and regulatory T cells in both resting 
state and in response to stimuli. In addition, we will investigate the contribution of 
specific genetic loci to intestinal dysfunction in proliferation, epithelial barrier 
integrity, autophagy, cellular stress responses and regenerative ability using gene-edited 
HIOs. Understanding how causal non-coding IBD risk variants disrupt key gene programs in human 
cells has potential to accelerate development of targeted therapeutic approaches.

## Key facts

- **NIH application ID:** 9942426
- **Project number:** 5R01DK119979-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Alexander Marson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $161,500
- **Award type:** 5
- **Project period:** 2018-09-18 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942426

## Citation

> US National Institutes of Health, RePORTER application 9942426, Functional Molecular Investigation of Inflammatory Bowel Disease (IBD) Risk Variants (5R01DK119979-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9942426. Licensed CC0.

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