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Mechanisms of peroxisome proliferator-activated receptor-alpha regulation in peridontitis

Award Number: R56DE032325
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: 09/08/2023
PERIOD OF PERFORMANCE END DATE: 09/07/2025

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Mechanisms of peroxisome proliferator-activated receptor-alpha regulation in peridontitis - Project Summary This application is for the extension of our current R03 grant titled “Pathogenic role of peroxisome proliferator- activated receptor alpha in periodontitis”, which has produced 2 published and 1 under review publications so far. Our studies have focused on the pathogenic role of PPARα in periodontal inflammation and bone resorption. Specifically, we demonstrated that PPARα not PPARβ or PPARγ had decreased expression levels in gingival cells stimulated with periodontitis antigens and in gingival tissue of mouse experimental periodontitis, and PPARα agonist treatment significantly reduces inflammation and bone loss in experimental periodontitis. While the mechanism of how activated PPARα regulates these pathology of periodontitis is largely unknown. Our recent data demonstrated that activation of PPARα inhibited the NF-kB (p65) signaling and increased the anti- inflammatory cytokines IL-10 and its secretion factor CD36 in the macrophages. The Wnt pathway was aberrantly activated in the macrophage during periodontitis in vivo and activated PPARα decreased Wnt/β-catinin/TCF-4 activity and induced a binding of β-catenin with PPARα in in vitro studies. Together with the previously published findings by others, we hypothesize that PPARα is an effective macrophage modulator through diversion the Wnt/β-catenin signaling via competing with TCF4 for binding to β-catenin, enhancing the CD36/IL-10 mediated anti-inflammatory transcriptional activities and suppressing the TCF4 mediated pro- inflammatory transcriptional activities. In this proposal, we will first determine if PPARα agonist’s periodontitis protective effect is via modulating macrophage polarization through a PPARα agonist dependent mechanism (Aim 1); Then we will explore the underlying mechanism by which PPARα modulates macrophage in the periodontitis (Aim 2). Successful completion of this project will generate conceptual advances in our understanding of the etiology of the disease by highlighting previously poorly understood pathways of inflammation. If our hypothesis is correct, these studies will broaden our insights into the potential role of PPARα in the regulation of macrophages in the inflammation of periodontal disease, as well as other immune-mediated osteolytic conditions such as osteoporosis or rheumatoid arthritis.


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	2023	ADA FORSYTH INSTITUTE, INC.	100 CHESTNUT ST FL 4	SOMERVILLE	MA	02143	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	1	2/5/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $497,500 )
2023	2023	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	1	9/8/2023	NEW	$497,500
2023	2023	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	1	9/26/2023	NEW	$0
														Subtotal = $497,500

Grand Total All Awards = $497,500

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Mechanisms of peroxisome proliferator-activated receptor-alpha regulation in peridontitis

Award Number: R56DE032325

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: 09/08/2023

PERIOD OF PERFORMANCE END DATE: 09/07/2025

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