# Heme allocation and disruptions in asthma and the failing heart

> **NIH NIH R00** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $244,020

## Abstract

The heme protein NADPH oxidase 5 (NOX5) is a transmembrane signaling enzyme which produces
superoxide in response to elevated intracellular calcium levels and is emerging as an exciting player in
immunity and the cardiovascular system. NOX5 is crucial for proper vascular contraction and appears to be
a nexus between cellular redox and calcium signaling, As the most recently discovered member of the
NOX family of enzymes, details of NOX5 regulation and its role in the cell remain poorly resolved. It has,
however, been implicated in numerous human diseases including cancers, diabetes and cardiovascular
disorders. Elucidating details of NOX5 regulation and its role in cardiovascular health and disease is crucial
to our understanding of normal cellular functions and how these become disrupted in disease. Based on
preliminary data from the K99 phase, the R00 phase will focus on investigating the role of NOX5 in
cardiomyocyte function and its contribution to the initiation and progression of atrial fibrillation (AF) (Aim 1)
and to probe the significance of novel protein:protein interactions identified in the K99 phase which link
NOX5 and the actin cytoskeleton, mitochondria, RNA regulation and stress response systems (Aim 2). Aim
1 will focus on understanding how NOX5 knockdown and overexpression affect gene and protein
expression, calcium flux, and cellular metabolism in induced pluripotent stem cell (iPSC) derived
cardiomyocytes, and then using patient tissue from hearts in AF or sinus rhythm to test hypothesizes
generated from the iPSC derived cardiomyocyte system. Aim 2 will use a model cell system (HEK293 cells
and HEK293 cells overexpressing NOX5) as well as iPSC derived cardiomyocytes to probe the interactome
of NOX5 in response to stimuli and to understand how these interactions affect NOX5 activity and
localization, the actin cytoskeleton, calcium flux, cellular metabolism, gene expression and the stress
response system. This project will uncover crucial details about the role of NOX5 in the heart and in the
broader context of cellular homeostasis. It will also lay important groundwork for identifying molecular
factors responsible for the switch between physiological and pathological responses and identify
interactions and interaction networks ideal for further study using purified components for use in
reconstitution assays, structural biology projects, mechanistic studies using biochemical approaches and
drug discovery projects.

## Key facts

- **NIH application ID:** 10756497
- **Project number:** 5R00HL144921-05
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Elizabeth A. Sweeny
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $244,020
- **Award type:** 5
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756497

## Citation

> US National Institutes of Health, RePORTER application 10756497, Heme allocation and disruptions in asthma and the failing heart (5R00HL144921-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10756497. Licensed CC0.

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