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G13 signaling attenuates periodontal inflammation and alveolar bone loss in the mouse model of age-associated periodontitis

Award Number: R01DE028264
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The goal of this study is to understand the mechanisms underlying how cell endogenous signaling regulates chronic inflammation and bone loss in aging-associated periodontitis. Periodontitis is one of the most common inflammatory diseases in humans that results in the destruction of periodontal tissues and alveolar bone which, ultimately results in teeth loss, especially in aged population, and potentially manifests into systemic conditions. Periodontal disease is inefficiently tackled by current therapeutics due to low response rates and adverse side effects presenting a significant challenge in the aging population. However, the mechanism underlying the role of Ga13 in inflammation diseases, including periodontal disease, especially under physiological aging and pathological periodontitis, as well as the molecular mechanism by which Ga13 regulates periodontal inflammation remains unknown. Current therapy is hindered by lack of understanding of the mechanisms underlying how physiological changes result in an age-associated reduction of periodontal tissues tissue functional capacity and contribute to increased incidence of periodontal disease. In our preliminary studies we found that the expression of Ga13) significantly decreases as mice age increases, and we revealed that Gna13f/fLysM-Cre mice exhibited severe bone loss with a significant increase in OC number, and PDL damage in periodontal disease lesions. We also found exacerbated alveolar bone loss and PDL damage associated with Gna13 deficiency in a periodontitis-induced model, while overexpression of local Gna13 constitutively active form (Gna13CA) resulted in reduced periodontal bone loss and inflammation and repaired PDL. Based on our preliminary studies, we hypothesize that Ga13 is a master negative regulator that inhibits periodontitis-induced chronic inflammation and bone loss through Ga13/RhoA/AKT/IKK/NF-¿B pathway and the increased Ga13 activate and signaling reduce the risk for age-associated periodontal disease. Three specific aims are proposed to test our hypothesis. In Aim 1, we will determine the function of Ga13 deficiency in monocytes on exacerbating periodontal inflammation and cementum, periodontal ligament (PDL), and alveolar bone loss by characterizing the phenotypes and pathomechanism of conditional knockout mouse models in aging-associated periodontitis. In Aim 2, we will define the function of Ga13 in monocytes on attenuating periodontal inflammation and periodontal ligament, cementum, and alveolar bone loss by characterizing the phenotypes and pathomechanism of Gna13OE transgenic mouse models and AAV mediated Ga13 local overexpression in aging-associated periodontitis. We will dissect the molecular mechanism by which Ga13 regulates periodontal inflammation and periodontal tissue and bone loss in age-associated periodontitis through Ga13/RhoA/AKT/IKK/NF-¿B, and integrins signaling pathways. The proposed study will provide important insights into the negative regulation of bone resorption and inflammation in aged-associated periodontitis by elucidating the underlying mechanism of Ga13 signaling.


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: 2024 ( Subtotal = $0 )
2024	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Oral Diseases and Disorders Research	000	5	4/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $349,065 )
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Oral Diseases and Disorders Research	005	5	5/25/2022	NON-COMPETING CONTINUATION	$349,065
2022	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Oral Diseases and Disorders Research	000	4	10/8/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Oral Diseases and Disorders Research	004	4	1/25/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Oral Diseases and Disorders Research	003	4	10/30/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$387,668
2022	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	002	3	10/30/2021	NON-COMPETING CONTINUATION	-$352,688
2022	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	001	2	10/30/2021	NON-COMPETING CONTINUATION	-$34,980
														Subtotal = $349,065

Issue Date FY: 2021 ( Subtotal = $361,000 )
2021	2021	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Oral Diseases and Disorders Research	001	4	7/2/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$361,000
2021	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	3	7/2/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $361,000

Issue Date FY: 2020 ( Subtotal = $352,688 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	3	5/15/2020	NON-COMPETING CONTINUATION	$352,688
														Subtotal = $352,688

Issue Date FY: 2019 ( Subtotal = $352,688 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	001	2	5/15/2019	NON-COMPETING CONTINUATION	$352,688
2019	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	1	2/19/2019	NEW	$0
														Subtotal = $352,688

Issue Date FY: 2018 ( Subtotal = $352,688 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	1	9/4/2018	NEW	$352,688
														Subtotal = $352,688

Grand Total All Awards = $1,768,129

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G13 signaling attenuates periodontal inflammation and alveolar bone loss in the mouse model of age-associated periodontitis

Award Number: R01DE028264

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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