# The role of macrophage metabolism and age in recovery from spinal cord injury

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $538,830

## Abstract

PROJECT SUMMARY/ABSTRACT
The average age at the time of spinal cord injury (SCI) has increased to 50.5 years old in the US. Observations
from several independent laboratories demonstrate that inflammation, specifically sustained pro-inflammatory
macrophage activation, contributes to age-related SCI deficits. In addition, it was recently discovered that the
efficacy of immunomodulatory SCI therapies is age-dependent. There is an urgent need to understand the
age-dependent mechanisms of sustained pro-inflammatory macrophage activation in SCI. The purpose of this
proposal is to investigate the role of macrophage bioenergetics in age-dependent inflammation and SCI
pathophysiology. The central hypothesis is that age-dependent impairments in macrophage metabolism drive
pro-inflammatory macrophage activation and contribute to secondary injury after SCI. The premise is that the
pyruvate dehydrogenase (PDH) pathway is a key regulator of pro- or anti-inflammatory macrophage activation
as a connecting link between glycolysis (pro-inflammatory) or oxidative phosphorylation (OXPHOS, i.e. TCA or
Krebs cycle activity; anti-inflammatory). PDH kinase (PDK) regulates PDH thereby serving as the gatekeeper
for OXPHOS. The hypothesis to be tested is that PDK inhibition will drive metabolic processes (i.e. increased
OXPHOS) required for reparative macrophage activation and improved SCI recovery by PDK. Accordingly,
three independent Aims are designed to selectively target macrophage metabolism mechanistically, using
chimerization with PDK knockout mice, and therapeutically, using a newly generated liposomal drug
formulation of dichloroacetate (DCA), a PDK inhibitor. 4 and 14-month-old mice will undergo T9 contusion SCI
to model the current SCI demographic. Aim 1 will identify PDH as a bottleneck for SCI macrophage
metabolism using a newly optimized purification approach that allows for isolation of macrophages after SCI
and assessment of extracellular acidification (ECAR, i.e. glycolysis) and oxygen consumption (OCR, i.e.
OXPHOS) rates using the Seahorse bioanalyzer. Aim 2 will identify metabolic targets for macrophage
dysfunction after SCI using state-of-the-art techniques including single-cell RNA-sequencing and in vivo Stable
Isotope-Resolved Metabolomics to determine the metabolic profiles of resident microglia and peripherally
derived macrophages. Aim 3 will identify PDK inhibition as a therapeutic target to treat SCI through evaluation
of anatomic and functional recovery. Completion of the proposed work will identify ways to harness the
reparative functions of CNS macrophages and improve clinical practice by refining translational treatment
strategies including age as a potential influence in SCI treatment and recovery. Understanding the extent to
which metabolic activity regulates macrophage function will provide insight into age-dependent CNS
inflammation, thereby advancing the fields of neurotrauma, neuroscience, and aging. Macrophage metabolism
is a contribu...

## Key facts

- **NIH application ID:** 10849854
- **Project number:** 5R01NS126228-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** JOHN C GENSEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $538,830
- **Award type:** 5
- **Project period:** 2023-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849854

## Citation

> US National Institutes of Health, RePORTER application 10849854, The role of macrophage metabolism and age in recovery from spinal cord injury (5R01NS126228-02). Retrieved via AI Analytics 2026-06-07 from https://api.ai-analytics.org/grant/nih/10849854. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*