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The Role of Histone Deacetylase 6 in Oral Bacteria-Mediated Periodontal Inflammation

Award Number: F31DE031968
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/25/2022
PERIOD OF PERFORMANCE END DATE: 03/24/2025

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The Role of Histone Deacetylase 6 in Oral Bacteria-Mediated Periodontal Inflammation - Project Summary/Abstract: Periodontitis is a chronic inflammatory disease induced by bacterial infection within the periodontium and affects almost 50% of adults in the United States. Unresolved inflammation in this area results in the breakdown of the periodontal ligament and alveolar bone which can lead to subsequent tooth loss. While the presence of bacteria initiates periodontitis, it is ultimately not the sole factor that drives disease progression. The inflammatory response is critical for the eradication of bacterial invaders, however the dysregulation of these mechanisms and overproduction of pro-inflammatory cytokines such as TNF-α, IL-6, IL-12 p40, and Macrophage Inflammatory Protein 2 (MIP-2) have been implicated in the progression of tissue damage in the periodontium and in other chronic inflammatory diseases. Histone deacetylase 6 (HDAC6) is a member of the class II HDACs located in the cytoplasm that can deacetylate specific non-histone proteins and facilitate their translocation to the nucleus. This deacetylation has been reported to alter production of inflammatory mediators in response to the stimulation of microbe-associated molecular patterns (MAMPs). Our preliminary results have shown that stimulation of innate immune cells with Porphyromonas gingivalis, a major pathogenic bacterium associated with chronic periodontitis, resulted in phosphorylation of class II HDACs and subsequent deacetylation of FoxO1, which will enhance its binding to the FoxO-binding element and thus promote associated pro-inflammatory mediator production. Likewise, selective inhibition of HDAC6 resulted in a decrease in pro-inflammatory cytokine production through increasing cytosolic translocation of FoxO1 and subsequently decreased its binding to the promoter of C/EBP-β after P. gingivalis infection. Therefore, using P. gingivalis as a model organism, we hypothesize that oral bacterial pathogens activate HDAC6 and enhance the inflammatory response through facilitating the deacetylation and nuclear translocation of FoxO1, subsequently enhancing the expression of downstream pro-inflammatory mediators. We will test this hypothesis using two aims. Experiments proposed for Aim 1 will investigate the role of HDAC6 in the inflammatory response by observing the production of inflammatory cytokines and the migration of neutrophils and will also delineate the downstream signaling of HDAC6 in different immune cells in response to P. gingivalis challenge. In Aim 2, we will examine the in vivo relevancy of HDAC6 signaling in gingival tissue inflammatory responses to oral bacterial infection and alveolar bone loss. These aims will establish the regulatory function of HDAC6-mediated differential inflammatory mediator secretion in the control of immune responses. The long-term goal of this proposed work will be to identify novel interventional therapeutic targets and regulatory mechanisms of periodontal inflammation that may be broadly applicable to other inflammatory diseases.


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 = $42,923 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Oral Diseases and Disorders Research	001	3	6/14/2024	NON-COMPETING CONTINUATION	$1,280
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Oral Diseases and Disorders Research	000	3	2/5/2024	NON-COMPETING CONTINUATION	$41,643
														Subtotal = $42,923

Issue Date FY: 2023 ( Subtotal = $41,643 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Oral Diseases and Disorders Research	000	2	2/9/2023	NON-COMPETING CONTINUATION	$41,593
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Oral Diseases and Disorders Research	001	2	2/28/2023	NON-COMPETING CONTINUATION	$50
														Subtotal = $41,643

Issue Date FY: 2022 ( Subtotal = $40,701 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Oral Diseases and Disorders Research	003	1	5/24/2022	NEW	-$1
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Oral Diseases and Disorders Research	000	1	2/9/2022	NEW	$39,985
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Oral Diseases and Disorders Research	001	1	2/9/2022	NEW	$0
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Oral Diseases and Disorders Research	002	1	4/20/2022	NEW	$717
														Subtotal = $40,701

Grand Total All Awards = $125,267

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The Role of Histone Deacetylase 6 in Oral Bacteria-Mediated Periodontal Inflammation

Award Number: F31DE031968

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/25/2022

PERIOD OF PERFORMANCE END DATE: 03/24/2025

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