# Integrative Genomic Analyses of Macrophages in Crohns Disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $759,420

## Abstract

Inflammatory bowel disease (IBD) results from a complex interplay of genetic, immunologic and microbial
factors and is comprised of Crohn's disease and ulcerative colitis subtypes. The over 140 loci associated to
Crohn's disease implicate key roles for innate immunity and macrophage regulation. Macrophages serve as
critical sentinels of the immune system embedded in each tissue, providing a key switch between tolerance
and activation. The immune cells that infiltrate Crohn's disease gut tissue are heavily influenced by the
interplay between cytokines and key transcription factors; however, understanding of macrophage gut-based
phenotype and regulatory state is presently limited. In Aim 1, we propose defining genotype-independent
mechanisms modulating intestinal macrophage phenotypes. We will expand understanding of intestinal
macrophage function in Crohn's disease through high dimensional mass cytometry (CyTOF) and through
epigenetic analyses of human macrophages from non-inflamed and inflamed intestine. CyTOF profiling of
tissue macrophages will elucidate macrophage subtypes. We have published the tissue-specific enhancer
landscape in mice and propose similar studies in human intestine. We hypothesize that Crohn's disease
associations will be particularly enriched within intestinal macrophage-specific enhancers and that mapping
these precise correlations with altered gene expression will provide critical insights into mechanisms of disease
pathogenesis. In Aim 2, we will develop of predictive network models that fully leverage naturally-occurring
genetic polymorphisms (SNPs as pertubagens) to elucidate the key drivers and biological mechanisms of
disease. In Aim 3, we propose defining mechanisms of macrophage phenotype and function by exploring
transcription factor and autocrine cytokine pathways associated to Crohn's disease and/or identified to be
regulated in studies from Aims 1 and 2. We have designed CRISPR vectors targeted to each of the 34 DNA
regulatory IBD loci genes expressed in intestinal macrophages to determine their effects on macrophage
hierarchies and inflammatory responses. Finally, we propose studies to define the role of IBD risk variants in
macrophage responses to microbial stimuli with a particular focus on rapid post-translational proteolytic events
affecting the autocrine TNF/TNFSF15 and IL1/IL18 cytokine pathways. Our multidisciplinary group with clinical,
human genetic, epigenetic, computational, immunological and technology development expertise will advance
understanding of the role of macrophages in Crohn's disease in a way that would not be possible by any single
group alone.

## Key facts

- **NIH application ID:** 9986747
- **Project number:** 5R01DK106593-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** JUDY H. CHO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $759,420
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986747

## Citation

> US National Institutes of Health, RePORTER application 9986747, Integrative Genomic Analyses of Macrophages in Crohns Disease (5R01DK106593-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9986747. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*