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Ceramide-mediated pathology in periodontitis

Award Number: R03DE027153
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: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 09/30/2021

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Ceramide-mediated pathology in periodontitis - ABSTRACT Ceramides in the cytoplasm of host cells are attracting interests as second messengers in a variety of cell events, especially pro-inflammatory response. However, membrane structures of most bacteria, as distinct from that of vertebrate, do not contain ceramide, indicating that production of ceramides by bacteria is rare. Nonetheless, phosphoglycerol dihydroceramide (PGDHC), but not LPS, produced by Porphyromonas gingivalis is found abundantly in the human periodontitis lesion. Contrast to the membrane impermeable ceramides derived from vertebrates, we reported that PGDHC penetrates the cellular membrane of host osteoclast precursor (OCP) and promotes cell fusion required for osteoclastogenesis by acting on a non-muscle myosin IIA (Myh9). Myh9 is an intracellular down-regulatory factor for cell fusion event in osteoclastogenesis. In contrast, it was also demonstrated that host ceramides directly act on cathepsin B to activate its catalytic activity. Furthermore, cathepsin B promotes RANKL-mediated osteoclastogenesis via temporally controlled proteolysis of Myh9 for initiation of cell fusion between OCPs. Our preliminary data demonstrated that PGDHC-mediated upregulation of osteoclastogenesis is attenuated by the chemical inhibitor for cathepsin B, indicating that cathepsin B is also engaged in the PGDHC-mediated osteoclastogenesis. Importantly, the intracellular levels of ceramides, either derived from host or bacteria, are regulated by ceramidases in the physiological context. Dysregulated function of acid ceramidase is implicated in the pathogenesis of Farber Disease and other medical complications. We discovered and published that expression of acid ceramidase in patients with periodontitis is diminished. Nonetheless, our knowledges about the ability of acid ceramidase to regulate the level of PGDHC as well as molecular mechanisms underlying PGDHC-mediated osteoclastogenesis are not yet understood well. Thus, we hypothesized that diminished aCDase activity in periodontal lesions retains the pathogenic property of tissue- penetrating PGDHC which, in turn, elevates the osteoclastogenesis via novel Cathepsin B/Myh9 axis in the bone resorption lesion of periodontitis. The Aim 1 is designed to test the protective role of acid ceramidase against PGDHC-mediated osteoclastognesis in a mouse model of periodontitis. We will evaluate the effect of endogenous acid ceramidase as well as exogenously administered recombinant acid ceramidase on neutralizing the PGDHC’s pathogenic activity. In Aim 2, using loss- and gain-of-function approaches, we will evaluate the engagement of cathepsin B in the PGDHC-mediated OCP fusion via Myh9 proteolysis. The proposed research project will, for the first time, elucidate the molecular mechanism underlying the pathogenically elevated periodontal bone loss targeting the unique P. gingivalis ceramides that promote osteoclastogenesis by modulating the cell fusion regulatory factor, Myh9, and investigate the effects of host-derived acid ceramidase that can potentially counteract such a pathogenic action of PGDHC.


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: 2022 ( Subtotal = $0 )
2022	2020	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	000	2	10/26/2021	SUPPLEMENT FOR EXPANSION	$0
2022	2020	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	001	2	5/20/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $279,233 )
2020	2020	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	001	2	7/17/2020	SUPPLEMENT FOR EXPANSION	$89,765
2020	2020	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	000	2	5/15/2020	NON-COMPETING CONTINUATION	$189,468
														Subtotal = $279,233

Issue Date FY: 2019 ( Subtotal = $248,276 )
2019	2019	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	001	1	8/5/2019	NEW	$0
2019	2019	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	002	1	8/15/2019	SUPPLEMENT FOR EXPANSION	$88,406
2019	2019	NOVA SOUTHEASTERN UNIVERSITY, INC.	3301 COLLEGE AVE	FORT LAUDERDALE	FL	33314	BROWARD	USA	Oral Diseases and Disorders Research	000	1	5/15/2019	NEW	$159,870
														Subtotal = $248,276

Grand Total All Awards = $527,509

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Ceramide-mediated pathology in periodontitis

Award Number: R03DE027153

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: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 09/30/2021

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