Impact of acid ceramidase activity on MIF-mediated migration of circulating osteoclast precursors to periodontal bone lesions in relation to aging

Information

  • Research Project
  • 10286664
  • ApplicationId
    10286664
  • Core Project Number
    R01AG064003
  • Full Project Number
    3R01AG064003-02S2
  • Serial Number
    064003
  • FOA Number
    PA-18-591
  • Sub Project Id
  • Project Start Date
    9/15/2019 - 4 years ago
  • Project End Date
    5/31/2023 - a year ago
  • Program Officer Name
    WILLIAMS, JOHN
  • Budget Start Date
    4/15/2021 - 3 years ago
  • Budget End Date
    5/31/2021 - 3 years ago
  • Fiscal Year
    2021
  • Support Year
    02
  • Suffix
    S2
  • Award Notice Date
    4/5/2021 - 3 years ago
Organizations

Impact of acid ceramidase activity on MIF-mediated migration of circulating osteoclast precursors to periodontal bone lesions in relation to aging

ABSTRACT This application will investigate the novel pathogenic host-bacterial interactions of which microglial-associated neuroinflammatory hallmarks of Late Onset Alzheimer?s disease (LOAD) emerges with periodontitis in relation to aging. The emerging evidence indicates that ligation of lipopolysaccharide (LPS) produced by the key periodontal pathogen Porphyromonas gingivalis, with Toll-Like Receptors-2 and -4 may serve as a risk factor for the initiation and/or progression of LOAD induced in young wild type mice. However, using the active R01 parent grant, we recently demonstrated that P. gingivalis-LPS/TLRs axis is attenuated in relation to aging, suggesting that an alternative pro-inflammatory mechanism may be engaged in the age-dependent pathologies, including LOAD. Our group also found that P. gingivalis produces a novel class of a host cell-membrane permeable ceramide lipid termed phosphoglycerol dihydroceramide (PGDHC) which elevates macrophage activation independently of TLRs. Furthermore, a study demonstrated that among the virulence factors produced by P. gingivalis, only PGDHC is found abundantly in the periodontal lesions as well as in the blood circulation. In addition, our preliminary data show that PGDHC is frequentely detected in the postmortem brains of patients with Alzheimer?s disease compared to that in healthy indviduals. Other preliminary results demonstrated that PGDHC elevates periodontal inflammation by acting on lysosomal protease Cathepsin B. Furthermore, it was reported that cathepsin B exacerbated the LOAD-like neuroinflammation and neurodegeneration in a mouse model of periodontitis induced by P. gingivalis. Although studies of Alzheimer?s disease pathology have predominantly focused on the amyloid-? and hyperphosphorylated tau, recent multidisciplinary findings strongly suggest that neuroinflammation associated with aberrant immune responses of the central nervous system (CNS) resident macrophages, microglia, is the third hallmark features of LOAD. However, it remains elusive whether PGDHC can promote microglia activation leading to the LOAD neuroinflammation. Based on these lines of evidence, we hypothesize that, in the context of LOAD-associated neuroinflammation, a novel PGDHC/Cathepsin B axis is engaged in the microglial activation. In the course of this one-year pilot study, we will investigate the impact of PGDHC on the cathepsin B-dependent activation of mouse primary microglia cells in vitro as well as the LOAD-like neuroinflammation and memory skills in relation to aging using female and male Cathepsin B-knock out and their wild type mice. Then, we will employ the single cell RNA-seq technology to identify transcriptome profiles between distinct subtypes of microglia isolated from the brains of wild type mice in relation to aging and sex. The proposed research project will, for the first time, establish the possible role of P. gingivalis-derived dihydroceramides in neuroinflammation and will provide a foundation for the development of a novel therapeutic approach for preventing periodontitis-associated cognitive decline in LOAD.

IC Name
NATIONAL INSTITUTE ON AGING
  • Activity
    R01
  • Administering IC
    AG
  • Application Type
    3
  • Direct Cost Amount
    250000
  • Indirect Cost Amount
    130000
  • Total Cost
    380000
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    866
  • Ed Inst. Type
    SCHOOLS OF DENTISTRY/ORAL HYGN
  • Funding ICs
    NIA:380000\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
  • Study Section Name
  • Organization Name
    NOVA SOUTHEASTERN UNIVERSITY
  • Organization Department
    MICROBIOLOGY/IMMUN/VIROLOGY
  • Organization DUNS
    002971240
  • Organization City
    Fort Lauderdale
  • Organization State
    FL
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    333147796
  • Organization District
    UNITED STATES