# The NET effect: Human CF epithelial responses to NETosis

> **NIH NIH K08** · UNIVERSITY OF CINCINNATI · 2021 · $169,312

## Abstract

Abstract
Neutrophils provide a critical defense against pathogens in CF, but neutrophil responses may
contribute to lung destruction and early death in CF. Neutrophil extracellular traps (NETs) kill
microorganisms such as P. aeruginosa, and NET components are increased in CF sputum.
There is a knowledge gap, however, regarding the signaling required for NETosis and how
NETs impact functions of human airway epithelia relevant to CF. Our central hypothesis is that
CF neutrophils have an increased propensity to form NETs and that NETs contribute to airway
epithelial cell injury in death in CF. To test this hypothesis, we will first generate homozygous
corrected CFTRdel508 iPS neutrophils using CRISPR/Cas genetic editing strategies for
“isogenic” comparisons of the impact of CFTR. This is a novel approach as human neutrophils
cannot be genetically modified. Then in Aim 1, we will examine the regulation of NETosis and
identify required pathways. We will also compare kinetics of NETosis and the composition of
NETs between uncorrected and corrected CFTRdel508 iPS neutrophils. In Aim 2, we will
determine the impact of NETosis on CF epithelial cell functions, including tight junction integrity,
cytokine expression and cell death. Next, we will ascertain how NETosis alters the airway
epithelial transcriptome, particularly expression of genes relevant to barrier function, cytokine
signaling and cell death. The contribution of this work will be to identify and reveal the biology of
novel, specific immunomodulatory targets in CF that could limit perpetuation of inflammation
and prevent progressive lung destruction in CF. Completion of these Aims will also generate
new insight into how NETs affect epithelial cell functions and the regulation of NETosis in
human neutrophils, which is important for many common diseases involving NETs. Finally,
completion of this project will provide crucial training to Dr. Hudock in genetic editing, airway cell
biology and transcriptomics that will help her develop an independent career.

## Key facts

- **NIH application ID:** 10238069
- **Project number:** 5K08HL124191-05
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Kristin Mara Hudock
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $169,312
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10238069

## Citation

> US National Institutes of Health, RePORTER application 10238069, The NET effect: Human CF epithelial responses to NETosis (5K08HL124191-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10238069. Licensed CC0.

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