# Intestinal single cell analyses and population differences in innate immunity in Crohn's disease drive treatment response and clinical heterogeneity: towards Precision IBD

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $736,014

## Abstract

Crohn's disease is a chronic, typically progressive inflammation most commonly affecting the terminal ileum. Of
the over 200 associated genetic loci, the three most significant Crohn's associations include NOD2, IL23R and
PTGER4. We present single cell RNASeq (scRNASeq) data from ileal tissues and blood involving over 100,000
transcriptomes and define a subset of treatment refractory patients expressing an inflammatory mononuclear
phagocyte (inf. MNP) module. This module includes inflammatory macrophages, activated fibroblasts, mature
dendritic cells, as well as activated T cells and IgG producing plasmablasts. In Aim 1, we will protein validate
and refine the inflammatory mononuclear phagocyte (inf. MNP) module through CITE-seq studies of ileal tissues
and peripheral blood. We will improve on present cell cluster classifications and provide a more fine-scale protein
validation through CITE-seq, where quantitative surface protein measurements will be performed on the same
cells for which scRNASeq data are obtained. By so doing, these new CITE-seq studies will a) refine and validate
transcriptome-based patient outcome definitions, b) refine key cell cluster definitions for relatively uncommon
cells (fibroblasts, dendritic cells), c) improve blood to tissue mappings of adaptive (T, B, and plasma cells)
immunity, and d) refine PTGER4 and IL23R gene expression, hypothesized to play major roles in treatment non-
response (Aim 3). In Aim 2, we will define early perturbations in macrophage-fibroblast cross-talk driven by
NOD2-deficiency and establish anti-TNF responsive mechanisms. NOD2 is an intracellular sensor of muramyl
dipeptide (MDP), the minimal bioactive component of bacterial peptidoglycan. We have observed co-expression
of NOD2 with cells expressing CD14 (blood monocyte marker) and high levels of collagens in individual cells;
this key finding informs the novel hypothesis that loss-of-function NOD2 pathogenicity is partly driven by a failure
to differentiate into residential macrophages, favoring more pluripotent stromal-type cells. In Aim 3, we seek to
accelerate progress towards precision Crohn's disease by leveraging cell-specific gene expression of IL23R and
PTGER4 to prioritize cellular and molecular salvage mechanisms in anti-TNF refractory patients. Despite
appreciable anti-IL12/23 salvage, substantial non-response remains. Leveraging this unmet medical need, we
will test for correlation of IL23R-expressing immune cells to anti-IL12/23 clinical response through analyses of
multiple existing and newly-collected bulk RNA datasets. We hypothesize that inflammatory macrophage to
IL23R-expressing cell cross talk mediates response to anti-IL12/23 blockade, but leaves pathogenicity via
aberrant in situ mature dendritic cell differentiation via PTGER4. These comparative analysis of anti-IL12/23
responders vs. non-responders, will highlight refractory cells and pathways to be prioritized for target
prioritization. This proposal combines the thre...

## Key facts

- **NIH application ID:** 10339391
- **Project number:** 5R01DK123758-03
- **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:** 2022
- **Award amount:** $736,014
- **Award type:** 5
- **Project period:** 2020-02-05 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339391

## Citation

> US National Institutes of Health, RePORTER application 10339391, Intestinal single cell analyses and population differences in innate immunity in Crohn's disease drive treatment response and clinical heterogeneity: towards Precision IBD (5R01DK123758-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10339391. Licensed CC0.

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