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Role of HIF-1 in intervertebral disc function

Award Number: R56AR055655
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2024
PERIOD OF PERFORMANCE END DATE: 09/30/2025

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Role of HIF-1 in intervertebral disc function - 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 transgenic mice in a HIF-1-independent fashion. We will study the influence of elevated HIF-1 activity and glycolytic flux on key metabolic regulators and their relationship to NP aging.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	16	3/19/2025	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $312,002 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	16	9/19/2024	COMPETING CONTINUATION	$312,002
														Subtotal = $312,002

Grand Total All Awards = $312,002

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Role of HIF-1 in intervertebral disc function

Award Number: R56AR055655

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/20/2024

PERIOD OF PERFORMANCE END DATE: 09/30/2025

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