# Na/H Exchanger in Microglial Metabolism and Function

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $385,621

## Abstract

PROJECT SUMMARY
This is our revised competitive renewal application (R01 NS048216-16 A1, 02-04-2005 to 01-28-2021), “Na/H
exchanger in microglial metabolism and function”. In this renewal proposal, we will study Na+/H+ exchanger
isoform 1 (NHE1) in regulating microglial immunometabolism and cellular function in brain tissue repair.
Microglial phagocytosis is important for debris clearance, remyelination, and synapse remodeling for tissue repair
in neurodegenerative diseases [stroke, vascular dementia, Alzheimer’s Disease (AD), ADRD, etc.]. Therefore,
modulating microglial phagocytosis functions presents a novel therapeutic strategy for neurodegenerative diseases.
However, to date, the mechanisms that govern coordinated regulation of microglial energy metabolism and
phagocytosis are not completely understood, filling this knowledge gap is the central scientific premise for our study.
We reported previously that NHE1 protein-mediated H+ efflux (in exchange of Na+ influx) alkalinizes intracellular
pH (pHi) in microglia, which promotes sustained NADPH oxidase (NOX2) activation because the latter is inhibited
by low pHi. We obtained the following new findings: 1). selective deletion of microglial Nhe1 in the Cx3cr1-CreER+/-
;Nhe1f/f (cKO) mice reduced pro-inflammatory microglial responses but increased their restorative transformation
after ischemic stroke; 2). Nhe1 cKO microglia exhibited increased oxidative phosphorylation (OXPHOS), post-
stroke phagocytosis and spine stripping activities; 3). bulk RNAseq transcriptome analysis showed that the cKO
microglia displayed significantly elevated genes encoding key rate-limiting enzymes for OXPHOS, the hallmark
LXR/RXR-APOE-TREM2 pathway genes for phagocytosis and cholesterol efflux, and genes for phagolysosomal
function; 4). the cKO stroke mice concurrently exhibited enhanced oligodendrogenesis and remyelination with
improved cognitive functions. These findings strongly suggest that microglial NHE1 activity is involved in regulating
microglial immunometabolism and functions in post-stroke brains and emerges as a novel therapeutic target. We
will test our hypothesis by investigating: 1) the impact of selective deletion of microglial Nhe1 in cKO mice on
phagocytosis transcriptomic and functional changes in post-stroke brains; 2) how Nhe1 cKO microglia enhance
phagocytosis and cholesterol efflux for remyelination in post-stroke brains; 3) how Nhe1 cKO microglia boost
mitochondrial biogenesis and OXPHOS to support cellular functions in post-stroke brains.
Impact, completion of this study will improve our understanding on coordinated regulation of immunometabolism
and cellular functions in microglia; and will shed light on NHE1 protein as a therapeutic target for promoting
restorative microglial metabolism and functions for brain tissue repair in neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10929305
- **Project number:** 5R01NS048216-18
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Dandan Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,621
- **Award type:** 5
- **Project period:** 2005-02-04 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929305

## Citation

> US National Institutes of Health, RePORTER application 10929305, Na/H Exchanger in Microglial Metabolism and Function (5R01NS048216-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10929305. Licensed CC0.

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