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Molecular Aspects of Oral Plaque Formation

Award Number: R01DE012505
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: 09/01/1998
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Molecular Aspects of Oral Plaque Formation - Abstract Polymicrobial infections are inherently more complex than monospecies infections, and this complexity has been a significant barrier to both a fuller appreciation of pathogenic mechanisms, and to the development of effective measures to control or prevent the disease. Periodontal diseases typify polymicrobial diseases, and are among the most common infections of humans. Although certain organisms, such as Porphyromonas gingivalis, are considered key pathogens, it is the polymicrobial community as a whole that initiates and drives the disease. Interspecies interactions within communities shape overall pathogenic potential, and work supported by this project has uncovered a dynamic and multilevel interaction between P. gingivalis and its community partners. The pathogenicity of P. gingivalis can be constrained by the streptococcal diffusible metabolite, para-amino benzoic acid (pABA), which is as a precursor of de novo folate synthesis in the physiologically essential one-carbon metabolism (OCM) pathway. However, as physically integrated communities develop, interspecies co-adhesion results in suppression of streptococcal pABA production, and additionally, partner organisms such as Streptococcus gordonii and Fusobacterium nucleatum, enhance overall community pathogenicity. Sensing of both pABA and interspecies physical contact by P. gingivalis is transduced through a protein tyrosine phosphorylation signaling circuit. The tyrosine kinase Ptk1 controls flux through OCM as well as the production of virulence factors, including the gingipain proteases which can modulate interactions with neutrophils. Indeed, Ptk1 is required for pathogenicity in both murine abscess and alveolar bone loss models of disease. In this proposal we will define the role of Ptk1 as a master regulator which can integrate OCM with pathogenicity. In the first Aim we will examine how Ptk1-mediated phosphorylation of gingipains is necessary for their processing and secretion. We will determine where non-phosphorylated gingipains remain localized in P. gingivalis and investigate which components of the type IX secretion system machinery malfunction in the absence of phosphorylation. Additionally, we will follow post-translational maturation of non-phosphorylated gingipains to uncover the role of phosphorylation in catalytic removal of the N-terminal peptide, the haemagglutinin domains, or the C- terminal domain as is required for the assembly of fully activated proteases. In the second Aim, we shall functionally dissect the contribution of phosphorylation to the activity of the pABA synthesis enzyme PabC, and decipher a negative feedback loop whereby pABA can inhibit Ptk1. Aim 3 will address the impact of Ptk1 on the activation state of neutrophils and their potential for tissue destructive responses to P. gingivalis. Completion of this project will provide novel insights into the context-dependent pathophysiology of P. gingivalis, which could ultimately be translated into therapeutic strategies designed to target the community-based pathogenesis that underlies periodontal 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: 2025 ( Subtotal = $443,193 )
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	001	28	5/9/2025	NON-COMPETING CONTINUATION	$44,319
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	000	28	3/24/2025	NON-COMPETING CONTINUATION	$398,874
														Subtotal = $443,193

Issue Date FY: 2024 ( Subtotal = $434,328 )
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	003	27	5/15/2024	NON-COMPETING CONTINUATION	$434,328
2024	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	002	26	1/17/2024	COMPETING CONTINUATION	$489,953
2024	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	001	25	1/17/2024	NON-COMPETING CONTINUATION	-$362,093
2024	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	000	24	1/17/2024	NON-COMPETING CONTINUATION	-$127,860
														Subtotal = $434,328

Issue Date FY: 2023 ( Subtotal = $443,193 )
2023	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	000	26	3/2/2023	COMPETING CONTINUATION	$443,193
														Subtotal = $443,193

Issue Date FY: 2022 ( Subtotal = $362,093 )
2022	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	001	25	4/28/2022	NON-COMPETING CONTINUATION	$32,918
2022	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	000	25	4/13/2022	NON-COMPETING CONTINUATION	$329,175
														Subtotal = $362,093

Issue Date FY: 2021 ( Subtotal = $365,750 )
2021	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	000	24	3/29/2021	NON-COMPETING CONTINUATION	$365,750
														Subtotal = $365,750

Issue Date FY: 2020 ( Subtotal = $365,750 )
2020	2020	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	000	23	5/19/2020	NON-COMPETING CONTINUATION	$365,750
														Subtotal = $365,750

Issue Date FY: 2019 ( Subtotal = $365,750 )
2019	2019	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	002	22	4/9/2019	NON-COMPETING CONTINUATION	$365,750
2019	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	001	21	12/3/2018	COMPETING CONTINUATION	$85,929
2019	2017	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	000	20	12/3/2018	NON-COMPETING CONTINUATION	-$85,929
														Subtotal = $365,750

Issue Date FY: 2018 ( Subtotal = $365,750 )
2018	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	000	21	3/7/2018	COMPETING CONTINUATION	$365,750
														Subtotal = $365,750

Issue Date FY: 2017 ( Subtotal = $375,000 )
2017	2017	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	003	20	4/24/2017	NON-COMPETING CONTINUATION	$337,500
2017	2017	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	004	20	5/26/2017	NON-COMPETING CONTINUATION	$37,500
2017	2016	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	002	19	2/6/2017	EXTENSION WITH OR WITHOUT FUNDS	$397,405
2017	2015	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	001	18	2/6/2017	NON-COMPETING CONTINUATION	-$375,000
2017	2014	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Oral Diseases and Disorders Research	000	17	2/6/2017	NON-COMPETING CONTINUATION	-$22,405
														Subtotal = $375,000

Issue Date FY: 2016 ( Subtotal = $375,000 )
2016	2016	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Oral Diseases and Disorders Research	000	19	4/12/2016	EXTENSION WITH OR WITHOUT FUNDS	$375,000
														Subtotal = $375,000

Issue Date FY: 2015 ( Subtotal = $375,000 )
2015	2015	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Oral Diseases and Disorders Research	000	18	3/30/2015	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2014 ( Subtotal = $375,000 )
2014	2014	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Oral Diseases and Disorders Research	000	17	4/9/2014	NON-COMPETING CONTINUATION	$375,000
														Subtotal = $375,000

Issue Date FY: 2013 ( Subtotal = $375,000 )
2013	2013	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Oral Diseases and Disorders Research	001	16	5/2/2013	COMPETING CONTINUATION	$375,000
2013	2012	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Oral Diseases and Disorders Research	000	15	4/26/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $375,000

Issue Date FY: 2012 ( Subtotal = $417,504 )
2012	2012	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Oral Diseases and Disorders Research	000	15	2/20/2012	NON-COMPETING CONTINUATION	$417,504
														Subtotal = $417,504

Issue Date FY: 2011 ( Subtotal = $409,651 )
2011	2011	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Oral Diseases and Disorders Research	002	14	5/27/2011	NON-COMPETING CONTINUATION	$404,713
2011	2010	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	001	12	3/4/2011	NON-COMPETING CONTINUATION	-$183,833
2011	2010	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Oral Diseases and Disorders Research	000	13	3/4/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$188,771
														Subtotal = $409,651

Issue Date FY: 2010 ( Subtotal = $351,137 )
2010	2010	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	12	2/19/2010	NON-COMPETING CONTINUATION	$351,137
														Subtotal = $351,137

Issue Date FY: 2009 ( Subtotal = $354,707 )
2009	2009	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	001	11	3/23/2009	NON-COMPETING CONTINUATION	$35,470
2009	2009	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Oral Diseases and Disorders Research	000	11	2/18/2009	NON-COMPETING CONTINUATION	$319,237
														Subtotal = $354,707

Issue Date FY: 2008 ( Subtotal = $366,354 ) (Continued on the next page)
Grand Total All Awards = $9,489,522

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Molecular Aspects of Oral Plaque Formation

Award Number: R01DE012505

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: 09/01/1998

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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