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Osteoimmunology of Retarded Bone Regeneration in Periodontitis

Award Number: R01DE029709
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Osteoimmunology of Retarded Bone Regeneration in Periodontitis - Retarded bone regeneration is characteristic to periodontitis. Even after successful conventional periodontal treatment, periodontal bone regeneration rarely, if ever, occurs, while molecular mechanism underlying retarded bone regeneration is largely unknown. This RO1 application proposes to exploit the osteoimmunological roles of osteoclast (OC)-specific cell membrane receptor, Osteoclast Stimulatory Transmembrane Protein (OCSTAMP) and Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) in retarded bone regeneration in periodontitis. During osteoclastic bone resorption, osteoblast (OB)-activation molecules, such as insulin-like growth factor (IGF), act as “coupling” factors released from demineralized bone matrix to ensure that the same amount of bone resorbed by OC is replaced by differentiation and activity of OB. Strong evidence suggests that this coupling mechanism is interrupted (‘uncoupled’) in periodontitis where pathogenic bone resorption exceeds reparative bone formation, resulting in retardation of bone regeneration. Our preliminary results showed that P. gingivalis may be engaged in retarded bone regeneration in periodontitis. A recent study reported that Semaphorin4D (Sema4D) produced by OC inhibits IGF-mediated osteogenesis by OB. The upstream molecular event(s) that induce(s)/upregulate(s) Sema4D expression by RANKL-activated osteoclast precursors (OCp), as well as the mechanism of Sema4D action on OB in the context of periodontitis, are unknown. We preliminary identify the ligand for OCSTAMP is produced by activated OCp, and the binding of this ligand with OCSTAMP elicits signals for Sema4D-expression. Furthermore, periodontal pathogen, P. gingivalis, appears to upregulate the Sema4D production from OCp by upregulating the generation of OCSTAMP ligand. Based on these preliminary findings and published evidence, we hypothesized that pathogenic activation of OCSTAMP by its ligand upregulate the production of Sema4D form OCp which, in turn, inhibits osteogenesis in periodontitis. To test our hypothesis, the following two Specific Aims are proposed. Aim 1: To elucidate the molecular mechanism underlying the generation of ligand for OC-STAMP, Aim 2: To assess the impact of OC-STAMP-activation on retarded bone regeneration in a mouse model of periodontitis induced by the combination of ligature attachment and P. gingivalis infection. This study will, for the first time, elucidate the pathologic osteoimmunological mechanism that interrupts new bone formation in alveolar bone affected by periodontitis, thus, representing a potential paradigm shift in the development of novel periodontitis 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: 2025 ( Subtotal = $76,697 )
2025	2025	NOVA SOUTHEASTERN UNIVERSITY, INC	3300 S UNIVERSITY DR	FT LAUDERDALE	FL	33328	BROWARD	USA	Oral Diseases and Disorders Research	000	5	10/28/2024	SUPPLEMENT FOR EXPANSION	$66,342
2025	2025	NOVA SOUTHEASTERN UNIVERSITY, INC	3300 S UNIVERSITY DR	FT LAUDERDALE	FL	33328	BROWARD	USA	Oral Diseases and Disorders Research	001	5	10/29/2024	SUPPLEMENT FOR EXPANSION	$10,355
														Subtotal = $76,697

Issue Date FY: 2024 ( Subtotal = $719,411 )
2024	2024	NOVA SOUTHEASTERN UNIVERSITY, INC	3300 S UNIVERSITY DR	FT LAUDERDALE	FL	33328	BROWARD	USA	Oral Diseases and Disorders Research	003	5	8/1/2024	NON-COMPETING CONTINUATION	$0
2024	2024	NOVA SOUTHEASTERN UNIVERSITY, INC	3300 S UNIVERSITY DR	FT LAUDERDALE	FL	33328	BROWARD	USA	Oral Diseases and Disorders Research	001	5	7/26/2024	SUPPLEMENT FOR EXPANSION	$365,631
2024	2024	NOVA SOUTHEASTERN UNIVERSITY, INC	3300 S UNIVERSITY DR	FT LAUDERDALE	FL	33328	BROWARD	USA	Oral Diseases and Disorders Research	000	5	7/2/2024	NON-COMPETING CONTINUATION	$353,780
2024	2023	NOVA SOUTHEASTERN UNIVERSITY, INC	3300 S UNIVERSITY DR	FT LAUDERDALE	FL	33328	BROWARD	USA	Oral Diseases and Disorders Research	002	4	7/29/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $719,411

Issue Date FY: 2023 ( Subtotal = $736,986 )
2023	2023	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	002	4	7/12/2023	SUPPLEMENT FOR EXPANSION	$10,355
2023	2023	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	001	4	7/10/2023	SUPPLEMENT FOR EXPANSION	$365,631
2023	2023	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	000	4	6/2/2023	NON-COMPETING CONTINUATION	$361,000
														Subtotal = $736,986

Issue Date FY: 2022 ( Subtotal = $439,352 )
2022	2022	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	000	3	7/29/2022	NON-COMPETING CONTINUATION	$357,390
2022	2022	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	002	3	8/3/2022	SUPPLEMENT FOR EXPANSION	$75,548
2022	2022	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	001	3	8/2/2022	SUPPLEMENT FOR EXPANSION	$6,414
														Subtotal = $439,352

Issue Date FY: 2021 ( Subtotal = $505,907 )
2021	2021	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	000	2	7/13/2021	NON-COMPETING CONTINUATION	$361,000
2021	2021	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	002	2	8/19/2021	SUPPLEMENT FOR EXPANSION	$70,571
2021	2021	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	001	2	8/10/2021	SUPPLEMENT FOR EXPANSION	$74,336
														Subtotal = $505,907

Issue Date FY: 2020 ( Subtotal = $348,094 )
2020	2020	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	000	1	7/17/2020	NEW	$348,094
														Subtotal = $348,094

Grand Total All Awards = $2,826,447

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Osteoimmunology of Retarded Bone Regeneration in Periodontitis

Award Number: R01DE029709

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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