# Mount Sinai School of Medicine Inflammatory Bowel Disease Genetics Research Center

> **NIH NIH U01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $168,252

## Abstract

Abstract
Refractory rectal fistulae are a major unmet medical need and disproportionately impact African-
American Crohn's disease patients for unknown reasons. The mainstay of therapy is anti-TNF
monoclonal antibodies; however, durable, fisula-free remission is achieved in only a minority of
patients. In this supplemental proposal, we hypothesize that the major effect players that
modulate susceptibility to perianal fistula include rectal epithelial cells and newly migrated
monocytes. Given the markedly distinct contributions for major effect, innate immune loci
between European (NOD2, IL23R, autophagy), Far East Asian (TNFSF15) and African-
American (PTGER4, LACC1, FCGR2A) Crohn's disease, combined with the marked induction
of the monokine CCL2 in inflamed rectum, in Aim 1, we seek to explore macrophage intrinsic
differences between African-American and European ancestry people driven by hypoxia and
muramyl dipeptide (MDP) stimulation. Once cell culture conditions are optimized to maximize
reproducibility and inter-individual variability, we will perform bulk RNASeq and Olink analyses,
and potentially scRNASeq. We seek to discover new, potentially rare, macrophage subtypes
that may reside within unique, chronic inflammatory milieus that may drive perianal fistula. In
Aim 2, we will compare IL-17A vs. IL-17C effects on epithelial cells and with macrophage co-
culture. Key readouts will be epithelial gap closure capacity with different levels of
differentiation, and transcripts modulating epithelial-mesenchymal transition (EMT). Finally, in
Aim 3, we will perform genetic association and transcriptome analyses in order to prioritize
additional contributing cell types driving severe rectal fistulae. We anticipate that blockade of
anti-IL12/23 in anti-TNF non-responders may not be as successful in salvaging responses
compared to with ileal Crohn's disease. However, if protective cell types and molecules can be
identified, local therapies to prevent peri-rectal fistulae formation acting directly on epithelial
cells may be developed.

## Key facts

- **NIH application ID:** 10193789
- **Project number:** 3U01DK062422-21S1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** JUDY H. CHO
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $168,252
- **Award type:** 3
- **Project period:** 2002-09-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10193789

## Citation

> US National Institutes of Health, RePORTER application 10193789, Mount Sinai School of Medicine Inflammatory Bowel Disease Genetics Research Center (3U01DK062422-21S1). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/10193789. Licensed CC0.

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