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The Role of VEGF in the Development of Low Back Pain Following IVD Injury

Award Number: R21AR081517
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: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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The Role of VEGF in the Development of Low Back Pain Following IVD Injury - Project Abstract Low back pain afflicts up to 80% of Americans and accounts for over $100 billion in healthcare and social costs annually. While intervertebral disc (IVD) degeneration and injury have been strongly associated with low back pain, the causation between pathoanatomical features of the IVD and clinical presentation of low back pain remains poorly understood. Recent rodent work show that axial low back pain symptoms can be recapitulated by the targeted injury of the lumbar intervertebral disc. The injury evokes a degenerative sequala in the IVD and produces neurite infiltration that are associated with chronic behavioral symptoms of axial low back pain. This is corroborated by human studies that observed increased innervation in degenerated IVD from humans. Thus, understanding the molecular events that drives IVD innervation may provide insights to therapeutic opportunities prior to the transition to chronic LBP symptoms. The proliferation of sensory nerves is tightly regulated by Nerve Growth Factor (NGF) and Vascular Endothelial Growth A (VEGFA). NGF serves critical homeostatic functions in neurons, while VEGFA plays a crucial role in spontaneous neurite extension and dendritic outgrowth in connective tissues, in addition to initiating angiogenesis. Degenerate and injured IVD cells express VEGFa as a part of the inflammatory cascade, but the mechanistic effects of VEGFA on neoinnervation in the IVD and subsequent low back pain behavior have not been investigated. The central hypothesis of this proposal is that the ablation of VEGFA attenuates neurite growth and vascularization into the injured IVD and alleviates ensuing low back pain symptoms. We will investigate the hypotheses through the following specific aims: Specific Aim 1: Determine whether the deletion of VEGFA 2-days after injury prevents IVD innervation and vascularization, and low back pain symptoms 3- and 12- weeks following a targeted injury. Specific Aim 2: Determine whether the deletion of VEGFA 6-weeks after injury slows, arrests, or reverses IVD innervation and vascularization, and low back pain symptoms 12- weeks following a targeted injury. The mechanistic understanding of VEGFA’s role in modifying the pathoanatomy will pave the way as a disease modifying therapy for low back pain. The ease for delivery anti-VEGF therapies makes it an attractive candidate for the diseased IVD, and anti-VEGFA has already been approved for the treatment of macular degeneration and cancer in humans. The proof-of-concept work here will also lay the foundation for future studies to investigate the source of VEGFA by utilizing tissue-specific drivers of CreERT2; the VEGF crosstalk between intervertebral disc, endothelial cells, and sensory neurons; and leveraging these chronic low back pain mechanisms as potential therapies.


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: 2024 ( Subtotal = $199,102 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/1/2024	NON-COMPETING CONTINUATION	$199,102
														Subtotal = $199,102

Issue Date FY: 2023 ( Subtotal = $171,591 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/27/2023	NEW	$171,591
														Subtotal = $171,591

Grand Total All Awards = $370,693

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The Role of VEGF in the Development of Low Back Pain Following IVD Injury

Award Number: R21AR081517

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: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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