# Role of HIF-1 in intervertebral disc function

> **NIH NIH R56** · THOMAS JEFFERSON UNIVERSITY · 2024 · $312,002

## Abstract

Our pioneering studies have shown that robust expression of HIF-1 allows NP cells to maintain their metabolism
and bioenergetic needs in the hypoxic intervertebral disc. The application is based on the recent observation that
dysregulation of HIF-1-dependent lactate export through a lactate efflux channel, MCT4 dramatically
influenced NP cell metabolism and promoted disc degeneration in MCT4-KO mice. We also found that the HIF-
1-dependent glucose importer GLUT1 is redundant in NP cells and functionally compensated by GLUT3.
Accordingly, a major goal of the investigation is to delineate the mechanisms by which HIF-1 governs glucose
availability and fine-tunes lactate/pyruvate metabolism in NP cells. Studies also address the possibility that age-
dependent decline in NP metabolic health can be retarded by elevating HIF-1 activity and glycolysis. In Aim 1
we will test the hypothesis that in the hypoxic microenvironment of the disc, GLUT3, is the primary HIF-1-
dependent glucose importer. We will determine the mechanisms by which HIF-1 controls the transcription of
GLUT3 and will measure glucose flux in GLUT3-deficient NP cells following the fate of [1-2-13C2]-glucose and
[U-13C5]-glutamine. Using Krt19CreERT driver we will generate and characterize NP-specific Glut3 and Glut1/3
double-knockout mice. In a parallel study, we will use human degenerated NP tissues and isolated cells to
determine how disease severity alters the expression of GLUTs and metabolic function. In Aim 2 we will test the
hypothesis that fine-tuning of lactate-pyruvate fate in glycolytic NP cells is regulated by a HIF-1-responsive
molecular circuit comprising lactate dehydrogenase (LDH), the mitochondrial pyruvate importer MPC1, and the
lactate exporter MCT4. Using loss-of-function experiments with Seahorse assays we will investigate how
modulating LDH-MPC1 axis alters NP cell metabolism. We will determine if dysregulation of lactate generation
(LDH) or pyruvate import (MPC1) into mitochondria alters glycolytic and TCA cycle flux using 13C-glucose and
13C-glutamine labeling. We will generate and characterize the phenotype of NP-specific LdhaK19CreER and
Mpc1K19CreER knockout mice to ascertain if this perturbation compromises disc health with aging. Finally, we will
use degenerated human NP tissues to determine how disease severity alters LDH and MPC1 expression and
correlate it to metabolic state. In Aim 3 we will test the hypothesis that in aged mice enhanced glycolytic flux and
fine-tuned lactate/pyruvate metabolism mitigate disc degeneration. We will examine the age-dependent changes
in disc phenotype by overexpressing the HIF-1dPA allele insensitive to PHD-mediated degradation in the NP of
14-month-old mice (HIF-1dPAK19CreERT). These mice will also be crossed with Glut3f/f mice to assess whether
glycolysis stimulation by increasing glucose influx underscores the beneficial effects of HIF-1dPA. Similarly, we
will stimulate glycolysis in 14- and 18-month-old TRE-Pfkfb3 tr...

## Key facts

- **NIH application ID:** 11175785
- **Project number:** 2R56AR055655-16A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Makarand V Risbud
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $312,002
- **Award type:** 2
- **Project period:** 2024-09-20 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11175785

## Citation

> US National Institutes of Health, RePORTER application 11175785, Role of HIF-1 in intervertebral disc function (2R56AR055655-16A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11175785. Licensed CC0.

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