# Bioenergetic regulation of the innate immune response after TBI

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2024 · —

## Abstract

Microglial/macrophage activation contributes to neuronal injury after traumatic brain injury (TBI),
primarily through release of cytokines, proteases, and reactive oxygen species. Recent studies
from our lab and others show that these aspects of microglia/macrophage activation can be
suppressed by limiting glucose flux through glycolysis. Activated microglia/macrophages are
unique among brain cells in that they primarily utilize hexokinase-2 (Hk2) rather than
hexokinase-1, thus enabling selective targeting of glycolysis in these cells. The over-riding aim
of this proposal is to determine if Hk2 inhibition can suppress pathogenic aspects of
microglial/macrophage activation and improve outcomes in a mouse model of TBI. We will
assess microglial gene expression, cytokine expression, oxidant production, and neural and
microvascular injury in transgenic mice in which Hk2 is selectively deleted in the
microglial/macrophage lineage, and in wild-type mice treated with Hk2 inhibitors at time points
after controlled cortical impact. A single Hk2 inhibitor will then be chosen for assessments of
long term histological and behavioral outcomes after TBI. We will place a particular focus on the
effects of these interventions on neurite (dendrite and axon) loss after TBI, as our findings to
date indicate inflammation to be a major determinant of neurite degeneration. In parallel, studies
using cultured microglia will assess the effects of Hk2 inhibition on overall glycolytic rate, gene
expression and pro- and anti-inflammatory processes. These studies will also evaluate a
potential mechanism by which glycolytic inhibition influences microglial/ macrophage activation.
Of note, selective Hk2 inhibitors are now entering clinical use for other purposes, thus facilitating
potential translation of these studies to clinical treatment of TBI.

## Key facts

- **NIH application ID:** 10805035
- **Project number:** 1I01BX006251-01A1
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** RAYMOND A SWANSON
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805035

## Citation

> US National Institutes of Health, RePORTER application 10805035, Bioenergetic regulation of the innate immune response after TBI (1I01BX006251-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10805035. Licensed CC0.

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