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Role of complement receptor C5L2 in reparative dentinogenesis

Award Number: R01DE029816
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: 03/23/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Role of complement receptor C5L2 in reparative dentinogenesis - Project Summary/Abstract Dental caries represents a common public health problem. Caries involves bacterial invasion, physicochemical dissolution and proteolysis of the mineral and protein components of teeth. Direct bacterial and byproduct interaction with dental pulp cells and odontoblasts in dentinal caries activates a protective repair process of ‘tertiary’ dentin formation. This process requires the recruitment and differentiation of dental pulp stem cells (DPSCs). Clinical therapies such as pulp capping aim to promote dentin regeneration and sustain pulp vitality and consequently endurance of the natural dentition. However, therapeutic dentin regeneration is elusive. The cellular and molecular mechanisms orchestrating dentin-pulp regeneration following infection are not fully elucidated, especially the role of inflammation on dentinogenesis. We have demonstrated that the complement system, which is an important mediator of inflammation and tissue regeneration, is activated in the caries process. A major role for complement and C5a binding to its receptor C5aR in responses to injury is well established. The C5a receptor- like 2 (C5L2) also participated in inflammatory reactions of several pathological conditions, yet, to date no investigation has explored the role of this enigmatic receptor in tissue regeneration and stem cell biology. Here, we propose a significant role for the complement system and C5L2 in DPSC odontoblastic differentiation and reparative dentin formation. Preliminary studies demonstrate that C5L2 expression by DPSCs is quickly increased during odontogenic differentiation, and this expression is potentiated by the inflammatory cytokine TNFα. Moreover, siRNA silencing of C5L2 expression in DPSCs significantly increases the expression of dentinogenic markers like DMP1 and DSPP during odontogenic differentiation. We provide further evidence that p38 map kinase (p38a) plays a key role in DPSC-mediated dentinogenesis. Here, we explore ways of enhancing this odontoblastic function of DPSCs via a novel C5L2 pathway involving p38a signaling. We will define the role of C5L2 in the odontoblastic differentiation of DPSC and characterize the mechanism of action of C5L2 during dentinogenesis. In vivo dentin formation will be evaluated using the mouse pulp-capping/caries model combined with the C5aR, C5L2 and DSPP/p38a knockout mice. The results obtained from this project will shed new light onto cellular and molecular events that orchestrate the initial steps of dentinogenesis by linking the inflammation to DPSC function through C5L2 and p38a pathways. These studies will provide the basis for future potential therapeutic interventions of dentin-pulp complex regeneration and vital tooth preservation.


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: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Oral Diseases and Disorders Research	000	4	12/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $466,030 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Oral Diseases and Disorders Research	001	4	5/7/2025	NON-COMPETING CONTINUATION	$46,603
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Oral Diseases and Disorders Research	000	4	3/11/2025	NON-COMPETING CONTINUATION	$419,427
														Subtotal = $466,030

Issue Date FY: 2024 ( Subtotal = $456,710 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Oral Diseases and Disorders Research	000	3	2/22/2024	NON-COMPETING CONTINUATION	$419,427
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Oral Diseases and Disorders Research	001	3	6/13/2024	NON-COMPETING CONTINUATION	$37,283
														Subtotal = $456,710

Issue Date FY: 2023 ( Subtotal = $571,614 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Oral Diseases and Disorders Research	001	2	2/21/2023	NON-COMPETING CONTINUATION	$466,030
2023	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Oral Diseases and Disorders Research	000	1	10/28/2022	NEW	$105,584
														Subtotal = $571,614

Issue Date FY: 2022 ( Subtotal = $487,950 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Oral Diseases and Disorders Research	000	1	3/23/2022	NEW	$487,950
														Subtotal = $487,950

Grand Total All Awards = $1,982,304

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Role of complement receptor C5L2 in reparative dentinogenesis

Award Number: R01DE029816

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: 03/23/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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