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Control of intervertebral disc degeneration via matrix-mediated delivery of platelet-derived growth factors

Award Number: R01AR076427
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Control of intervertebral disc degeneration via matrix-mediated delivery of platelet-derived growth factors - Summary There is no successful biologic treatment for intervertebral disc degeneration (IDD). The goal of this proposal is to utilize a hydrogel-based engineering approach to deliver PDGF to intervertebral disc (IVD) tissue and establish PDGF as a potent inhibitor of IDD. We also aim to define the mechanisms underlying its effects on normal and diseased nucleus pulposus (NP) and annulus fibrosus (AF) cells using human IVDs as well as preclinical models of IDD. The scientific premise for the proposed work is a rigorous body of published evidence demonstrating that PDGF- BB, as well as PDGF-AB can stimulate disc cell growth and/or inhibit their programmed cell death in vitro. Our compelling preliminary data in vivo point to an anti-apoptotic effect of PDGF-BB in a rabbit puncture model, which led to restored disc height and enhanced mechanical properties of the treated discs compared to untreated controls. It is based on these encouraging data and other molecular preliminary data demonstrating that these anti-apoptotic effects may be mediated through the transcription factor Runx1, that we postulate the novel hypothesis that sustained exposure of the NP and AF to PDGF will repress IDD progression through controlling Runx1 activity. To test this hypothesis, we will first compare the effects of PDGF-BB and PDGF-AB on normal versus diseased human AF and NP cells cultured in high density. We will then determine the molecular mechanisms underlying the anti-degenerative effects of PDGF on disc cells through transcriptomic and functional analyses involving RUNX1 and other signaling molecules (Aim 1A). The validation of Runx1 function in PDGF-mediated effects will also be examined in vivo using a new gain of function mouse model (Aim 1B). In the second Aim, we will fabricate and validate the functionality of an injectable biomaterial capable of sustaining the exposure of disc cells to PDGF-BB (Aim 2A). We will then establish therapeutic modalities for long-term inhibition of IDD in vivo by PDGF-BB using a rabbit disc puncture model (Aim 2B). Our proposed work will provide seminal information about the mechanisms underlying PDGF’s effects on the IVD and the role of Runx1 in IDD. The mechanistic data will help identify new therapeutic targets to treat IDD.


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 = $329,557 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/4/2025	NON-COMPETING CONTINUATION	$329,557
														Subtotal = $329,557

Issue Date FY: 2024 ( Subtotal = $397,114 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/7/2024	NON-COMPETING CONTINUATION	$28,657
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	3/28/2024	NON-COMPETING CONTINUATION	$368,457
														Subtotal = $397,114

Issue Date FY: 2023 ( Subtotal = $422,800 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	3/3/2023	NON-COMPETING CONTINUATION	$422,800
														Subtotal = $422,800

Issue Date FY: 2022 ( Subtotal = $423,936 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/28/2022	NON-COMPETING CONTINUATION	$423,936
														Subtotal = $423,936

Issue Date FY: 2021 ( Subtotal = $442,413 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/25/2021	NEW	$442,413
														Subtotal = $442,413

Grand Total All Awards = $2,015,820

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Control of intervertebral disc degeneration via matrix-mediated delivery of platelet-derived growth factors

Award Number: R01AR076427

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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