# Identifying Neutrophil Specific Mechanisms for Resistance to Biologics in Ulcerative Colitis

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $698,096

## Abstract

Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting approximately 1 million people in the
United States. Annual healthcare expenditure for UC is estimated to be more than $10 billion dollars, with most
of this cost being related to expensive biologic therapies. The two most prescribed biologics in UC are
vedolizumab and adalimumab, however, efficacy for these advanced therapies plateaus at approximately 30%.
Thus, there is an unmet need to understand drug specific mechanisms of treatment resistance. Our participant
level patient data and observations in murine colitis/colon injury models indicate that persistence of distinct
neutrophil subsets in the intra-epithelial space results in ongoing intestinal stem cell (ISC) injury, negatively
impacting the epithelial crypt microenvironment and treatment efficacy for biologics. Thus, proposed studies will
integrate clinical patient-focused and basic mechanism-focused studies to explore the idea that spatially distinct
neutrophil populations with unique genetic signatures and function may dictate mechanism specific therapeutic
response and impact mucosal injury resolution.
In the first Aim using spatially resolved single-cell and sub-cellular high-plex digital quantification of mRNA and
protein in already collected mucosal tissue from UC patients, we will profile neutrophils, T-cells, and intestinal
epithelium based on spatial orientation (crypts vs lamina propria) in UC patients. Using this approach, we will
identify gene/protein signatures predictive of response to vedolizumab therapy in UC and define targetable
mechanisms through which epithelial neutrophils interact with crypts and T-cells to mediate non-response to
vedolizumab. Second Aim will investigate how intra-epithelial neutrophil burden functionally impacts therapeutic
responses and resolution of colon injury in murine colitis. Specifically, using murine colon injury/colitis models,
clinically relevant therapeutics and neutrophil-specific genetic approaches, we will define molecular cues guiding
neutrophil retention in the intra-epithelial space and how this unique spatial localization impacts therapeutic
response to biologics (vedolizumab, adalimumab and tofacitinib). We will further determine whether intra-
epithelial neutrophils exacerbate colon injury and impede therapeutic efficacy of vedolizumab through enhanced
ISC loss.
As such, studies outlined in the current proposal will identify new mechanisms of therapeutic resistance to
biologics and identify molecular targets to optimize/improve responsiveness.

## Key facts

- **NIH application ID:** 10634286
- **Project number:** 1R01DK135620-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Parambir Singh Dulai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $698,096
- **Award type:** 1
- **Project period:** 2023-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10634286

## Citation

> US National Institutes of Health, RePORTER application 10634286, Identifying Neutrophil Specific Mechanisms for Resistance to Biologics in Ulcerative Colitis (1R01DK135620-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10634286. Licensed CC0.

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