# Metabolic adaption of macrophages to heme detoxification in systemic vascular inflammation

> **NIH NIH R56** · UNIVERSITY OF VIRGINIA · 2022 · $517,372

## Abstract

SUMMARY
Hemolysis accompanies many pathologies including trauma, sepsis, hemorrhagic stroke, malaria, and genetic
disorders such as sickle cell disease (SCD) and glucose-6-phosphate dehydrogenase (G6PD) deficiency. The
release of free heme into the circulation promotes numerous vascular pathologies and therefore, efficient heme
clearance and detoxification is necessary to prevent sustained tissue damage. Chronic hemolysis results in
vascular inflammation driven by free heme, accompanied by oxidative tissue damage, which may lead to
generation of oxidized phospholipids that are implicated in atherosclerosis and cardiometabolic disease
complications. Here, we will test the overall hypothesis that in settings of hemolytic stress, G6PD deficiency
becomes increasingly detrimental due to dysfunctional metabolic adaptation, and that metabolic adaptation of
macrophages and monocytes is essential for the resolution of hemorrhage in SCD.
In specific aim 1 we will test the hypothesis that metabolic adaptation in macrophages is necessary for efficient
heme-clearance and cell survival and to determine the molecular mechanisms that regulate the metabolic shift
to the PPP in the context of hemolysis. We will also examine the consequences of insufficient heme detoxification
for cell survival and lipid oxidation in systemic hemolysis in G6PD and Steap3 transgenic mice and test the
hypothesis that the phosphofructokinase PBFKB3 is the target for CO to activate the PPP. In specific aim 2 we
will demonstrate the significance of metabolic adaptation to heme detoxification in SCD. We will examine
metabolic shift in murine models of SCD and characterize blood monocyte metabolic state in SCD patients.
These studies will identify novel therapeutic targets to improve heme detoxification and ameliorate heme-induced
oxidative tissue damage.

## Key facts

- **NIH application ID:** 10705347
- **Project number:** 1R56HL158886-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** NORBERT LEITINGER
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $517,372
- **Award type:** 1
- **Project period:** 2022-09-22 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705347

## Citation

> US National Institutes of Health, RePORTER application 10705347, Metabolic adaption of macrophages to heme detoxification in systemic vascular inflammation (1R56HL158886-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10705347. Licensed CC0.

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