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Pathogenesis of Inflammation-driven Intervertebral Disc Herniation: The Role of Syndecan 4

Award Number: R01AR074813
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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Pathogenesis of Inflammation-driven Intervertebral Disc Herniation: The Role of Syndecan 4 - The relationship between the etiology of intervertebral disc degeneration and low back pain has been subjected to considerable scrutiny. Degeneration is thought to be initiated by the abnormal production of a number of pro-inflammatory cytokines, in particular TNF-α and IL-1β. While these studies have shown involvement of cytokines in pathogenesis of disc degeneration and herniation, progress has been slow in delineating new therapeutic targets to block inflammation. This deficit stems from our lack of understanding of molecular mediators that regulate and link cytokine-dependent matrix degradation with immune cell migration into the disc through annular defects. Interestingly, our ongoing work has found an unexpected synergism between heparan sulfate (HS) proteoglycan syndecan4 (SDC4) and these two key inflammatory cytokines. The goal of the proposed investigations is to build on the central role of SDC4 in the pathogenesis of the disc herniation and inflammation. We have formulated two interrelated hypotheses each of which addresses a separate but linked phase of the disease process. The first phase relates to the effect of the inflammatory cytokines on the regulation of aggrecan rich matrix degradation. We will test the hypothesis that SDC4 through HS side chains promotes cytokine-dependent aggrecan rich matrix degradation through ADAMTS and MMP activation. Using gain and loss-of-function studies of SDC4 in NP cells treated with cytokines and RNA-Seq approach we will identify novel SDC4 responsive genes. We will also measure the contribution of MMPs, ADAMTS-1 and ADAM17 produced by NP cells in SDC4 shedding. In addition, we will determine how changes in SDC4 levels relate to aggrecan and collagen turnover in human tissues. The second stage of the disease process is characterized by structural changes in the NP and AF and formation of annular tears and herniations. We propose to test the hypothesis that that in inflammatory milieu of the herniated disc, SDC4 plays an important role in macrophage activation and migration by controlling the activity of select chemokines (CCL5, IL-8 and SDF-1) secreted by the disc cells. This will be achieved using primary macrophages isolated from SDC4-/- mice. Using well characterized painful human disc tissues, we will link changes in chemokines and SDC4 levels to immune cell activation, infiltration and matrix degradation. Finally, to explore the in vivo importance of SDC4 in pathogenesis of TNF--driven disc herniation, we will cross hTNFtg mice with SDC4 -/- animals to generate hTNFtg,SDC4-/- mice. To establish if a deficiency in SDC4 provides protection against cytokine-dependent disc herniation, we will compare molecular, structural and biomechanical properties of the motion segments with that of hTNFtg. To our knowledge, this would be the first attempt to address the contribution of SDC4 to mechanisms linking initiation and propagation of the degenerative cascade and herniation driven by inflammatory cytokines. These studies will provide a foundation for future development of interventional strategies to target SDC4 dependent catabolic and inflammatory phases of degenerative disc disease.


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: 2023 ( Subtotal = $450,879 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/25/2023	NON-COMPETING CONTINUATION	$405,792
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	2/17/2023	NON-COMPETING CONTINUATION	$45,087
														Subtotal = $450,879

Issue Date FY: 2022 ( Subtotal = $446,372 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/17/2022	NON-COMPETING CONTINUATION	$40,581
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/20/2022	NON-COMPETING CONTINUATION	$405,791
														Subtotal = $446,372

Issue Date FY: 2021 ( Subtotal = $457,991 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	7/20/2021	NON-COMPETING CONTINUATION	$33,049
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/28/2021	NON-COMPETING CONTINUATION	$424,942
														Subtotal = $457,991

Issue Date FY: 2020 ( Subtotal = $462,548 )
2020	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/28/2020	NON-COMPETING CONTINUATION	$416,293
2020	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	4/24/2020	NON-COMPETING CONTINUATION	$46,255
														Subtotal = $462,548

Issue Date FY: 2019 ( Subtotal = $462,548 )
2019	2019	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/18/2019	NEW	$462,548
														Subtotal = $462,548

Grand Total All Awards = $2,280,338

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Pathogenesis of Inflammation-driven Intervertebral Disc Herniation: The Role of Syndecan 4

Award Number: R01AR074813

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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