# Role of peptidylarginine deiminase in modulating macrophage functions in sepsis

> **NIH NIH F32** · NORTHWESTERN UNIVERSITY · 2023 · $31,295

## Abstract

Project Summary
Sepsis is a life-threatening organ dysfunction caused by a multifaceted dysregulated host response to an
infection, including sepsis induced acute lung injury (sepsis-ALI). Sepsis is the most common cause of in-
hospital deaths and costs more than $24 billion annually in the US. No specific therapy exists to prevent or
treat the cellular dysfunction associated with sepsis and sepsis-ALI. While the complex mechanisms of sepsis
have remained poorly defined, an emerging pathogenesis of sepsis and sepsis-ALI involves neutrophil and
macrophage cell death causing inflammation and organ damage through the release of citrullinated histone 3
release (CitH3). Petidylarginine deiminase (PAD) 2 and 4 catalyze the formation of CitH3. PAD2 and CitH3
have been linked to sepsis with findings of elevated serum levels of PAD2 and CitH3 in septic patients. Mouse
models have further demonstrated that knockout of Pad2 and utilization of pan-PAD inhibitors improved
survival and prevented organ dysfunction in several different sepsis models. Throughout the past decade, Dr.
Alam and Dr. Li have conducted extensive work on the PAD-CitH3 pathway in sepsis. This proposal is linked to
the NIH R01 proposal (1R01HL155116-01A1) “PAD2 and CitH3 in Pathogenesis of Sepsis-induced ALI” by Dr.
Alam and Dr. Li with a specific focus on elucidating the mechanisms of PAD and their physiologic impacts and
modulation of macrophages in sepsis. In Aim 1, we will conduct experiments using Pad 2-/-, Pad4-/-, and
Pad2-/-Pad4-/- mice to investigate the interaction of PAD2 and PAD4 in sepsis and sepsis-ALI outcomes. In
Aim 2, we will use adeno-associated virus (AAV)- mediated delivery of Cas9/gRNA to perform targeted
knockout and restoration of Pad2 in macrophages. Outcomes of mice with sepsis and their macrophage
activity with somatic ablation and targeted RNA knockout will be compared to assess possible compensatory
changes in mice with somatic ablation. For Aim 3, we will use RNA sequencing and proteomics to identify
genes associated with the compensation of Pad2 ablation. The knowledge gained from this project will have a
significant impact on our understanding of the PAD-CitH3 pathway in sepsis. This will contribute significant
insight in to the pathogenesis and potential treatment of sepsis, sepsis-ALI, and sepsis induced multi-organ
dysfunction.

## Key facts

- **NIH application ID:** 10705016
- **Project number:** 5F32HL162378-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Jessie W Ho
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $31,295
- **Award type:** 5
- **Project period:** 2022-03-01 → 2023-07-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705016

## Citation

> US National Institutes of Health, RePORTER application 10705016, Role of peptidylarginine deiminase in modulating macrophage functions in sepsis (5F32HL162378-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10705016. Licensed CC0.

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