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Role of Developmental Signaling Pathways in Maintenance of Spinal Discs

Award Number: R01AG070079
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Role of Developmental Signaling Pathways in Maintenance of Spinal Discs - PROJECT SUMMARY/ ABSTRACT Aging is a significant risk factor for the onset of several degenerative diseases, including spinal or intervertebral disc (IVD) degeneration and associated chronic back pain. IVD degeneration and chronic back pain are top neurological disorders and substantial financial burden, but with no therapy or cure. Each IVD has a central core of nucleus pulposus (NP), surrounded by orthogonal layers of annulus fibrosus (AF), together sandwiched between a pair of endplates that connect the IVD to the vertebral bodies. Much remains to be learned about the critical regulators of IVD growth, maturation, and maintenance, and whether their loss with age results in IVD pathologies. We will use conditional genetic mouse models, lineage tracing, heterochronic IVD organ culture, analysis of human disc samples, and unbiased approaches of high throughput transcriptomics to identify crucial developmental regulators', including sonic hedgehog (SHH), in IVD maintenance to fill in these gaps. Our central hypothesis is that Shh-expression by the NP cells is essential for growth and maturation of the IVD, and its age-related loss leads to the IVD pathologies. The expression of SHH signaling ligand by the notochord is crucial for embryogenesis. Previously, we showed that postnatal NP cells continue to express SHH, and SHH signaling regulates NP cell proliferation and ECM production by NP and AF. Though all NP cells are descendants of Shh-expressing notochord cells, our preliminary data reveals that most of them turn-off Shh expression after birth. Besides, age-related decline in Shh expression is associated with terminal differentiation of NP cells into multinucleated syncytium and subsequent loss along with the declined expression of ECM proteins that are important for IVD function. Our preliminary data also show that conditional targeting of Shh in adult mice accelerates IVD aging, along with the loss of NP cells, providing the logical premise for this new project. These data indicate that SHH signaling is crucial; however, we do not know its precise function during growth and maturation and whether it is critical for aging IVDs. Aim 1 will test the hypothesis that SHH is a critical signaling pathway and its downstream regulators play a distinct role during infancy and maturation, and its loss causes IVD pathologies. Aim 2 will test the hypothesis that Shh-expressing NP cells are the progenitor cells, and the stochastic expression of Shh regulates all NP cells' molecular heterogeneity. Aim 3 will investigate the beneficial effects of SHH signaling for delaying aging. We expect that the completion of this study will provide insights into the role of SHH as a critical regulator of growth and maturation of the IVD and identify avenues for targeting such molecules to reverse or delay the aging process and improve the quality of life of the aging population.


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	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	4	5/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $647,970 )
2024	2024	THE HOSPITAL FOR SPECIAL SURGERY FUND, INC.	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	4	4/19/2024	NON-COMPETING CONTINUATION	$647,970
														Subtotal = $647,970

Issue Date FY: 2023 ( Subtotal = $630,035 )
2023	2023	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	3	4/27/2023	NON-COMPETING CONTINUATION	$630,035
														Subtotal = $630,035

Issue Date FY: 2022 ( Subtotal = $708,853 )
2022	2022	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	2	4/14/2022	NON-COMPETING CONTINUATION	$708,853
														Subtotal = $708,853

Issue Date FY: 2021 ( Subtotal = $687,251 )
2021	2021	HOSPITAL FOR SPECIAL SURGERY FUND, INC., THE	535 E 70TH ST	NEW YORK	NY	10021	NEW YORK	USA	Aging Research	000	1	8/13/2021	NEW	$687,251
														Subtotal = $687,251

Grand Total All Awards = $2,674,109

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Role of Developmental Signaling Pathways in Maintenance of Spinal Discs

Award Number: R01AG070079

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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