Ceramide-mediated pathology in periodontitis

Information

  • Research Project
  • 10199552
  • ApplicationId
    10199552
  • Core Project Number
    R03DE027153
  • Full Project Number
    3R03DE027153-02S1
  • Serial Number
    027153
  • FOA Number
    PA-20-222
  • Sub Project Id
  • Project Start Date
    9/1/2020 - 3 years ago
  • Project End Date
    5/31/2021 - 3 years ago
  • Program Officer Name
    CHANDER, PREETHI
  • Budget Start Date
    9/1/2020 - 3 years ago
  • Budget End Date
    5/31/2021 - 3 years ago
  • Fiscal Year
    2020
  • Support Year
    02
  • Suffix
    S1
  • Award Notice Date
    7/17/2020 - 3 years ago
Organizations

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.

IC Name
NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
  • Activity
    R03
  • Administering IC
    DE
  • Application Type
    3
  • Direct Cost Amount
    59056
  • Indirect Cost Amount
    30709
  • Total Cost
    89765
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    121
  • Ed Inst. Type
    SCHOOLS OF DENTISTRY/ORAL HYGN
  • Funding ICs
    NIDCR:89765\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
  • Study Section Name
  • Organization Name
    NOVA SOUTHEASTERN UNIVERSITY
  • Organization Department
    DENTISTRY
  • Organization DUNS
    002971240
  • Organization City
    Fort Lauderdale
  • Organization State
    FL
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    333147796
  • Organization District
    UNITED STATES