Aging occurs with development of low-grade systemic inflammation, called ?inflammaging,? which is considered as a predictor of age-associated pathologies, including atherosclerosis, type II diabetes, and dementia, obesity, and cancer. Likewise, inflammaging manifests in the oral cavity, as evinced in increased incidence of periapical bone loss from pulpal infection in the aged population. Furthermore, the prevalence and severity of periodontitis is directly related with aging. The goal of this application is to elucidate the molecular mechanism that regulates inflammaging in the context of oral inflammatory conditions, e.g., pulpal infection and periodontitis, and to identify potential markers and therapeutic targets in aging-associated diseases. Growing evidence suggests a dynamic role of histone Lys-specific demethylases (KDMs) in diverse biological processes, including aging and inflammation. We identified KDM3C as a potential immunomodulatory factor that may regulate oral inflammatory responses in aging. Our preliminary study demonstrates that Kdm3C ablation increased the production of pro- inflammatory cytokines with endotoxin challenge; increased periapical and periodontal bone loss in Kdm3C knockout (ko) mice; and precipitous loss of endogenous KDM3C expression in aged tissues. These exciting preliminary data raise a novel hypothesis that KDM3C is an epigenetic, immunomodulatory factor that suppresses oral and systemic inflammation. We also hypothesize that loss of KDM3C during aging mediates elevated inflammatory responses to oral infection. To test this hypothesis, we will determine the role of KDM3C in oral and systemic inflammation during aging using pulpal exposure or experimental periodontitis model in young, old, and Kdm3C ko mice. Epigenetic role of KDM3C in oral inflammatory responses will be assessed by probing the enrichment levels of histone marks on the pro-inflammatory gene promoters. Also, we will determine the role of KDM3C in macrophage polarization and CD4+ Th lineage-specific differentiation in oral inflammatory lesions during aging. Macrophage plays multifunctional yet focal roles in the immune defense against oral bacterial infection. Our data suggest pro-inflammatory effects of Kdm3C ko on macrophage phenotype. Since KDM3C is precipitously lost during aging, suppression of KDM3C may alter the macrophage function, and the adaptive immune cell phenotype during aging. We will utilize the pulp exposure and ligature-induced periodontitis models in young, old, and Kdm3C ko mice to profile the immune cells within the periapical or periodontal lesions. Using bone marrow-derived macrophages isolated from young, old, and Kdm3C ko mice, we will compare the changes in macrophage polarization and CD4+ Th cell lineage-specific differentiation. These proposed experiments will elucidate the epigenetic role of KDM3C as an immunomodulatory factor in dentoalveolar tissues, and how aging perturbs the balance in pro-inflammatory and anti-inflammatory networks, resulting increased alveolar bone destruction in oral lesions. The outcome of this project will provide critical foundational data, upon which to build future R01 projects with clear translational potential to mitigate the aging-associated pathologies.

Public Health Relevance

The proposed research will lead to understanding the epigenetic role of histone demethylases (KDM3C) in regulation of proinflammatory cytokine gene expression in oral inflammatory lesions during aging. The outcome will be useful for development of novel therapeutics to control oral inflammatory conditions in the aged population so as to promote healthy aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DE028269-01
Application #
9636851
Study Section
Special Emphasis Panel (ZDE1)
Program Officer
Chander, Preethi
Project Start
2018-09-04
Project End
2020-08-31
Budget Start
2018-09-04
Budget End
2019-08-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095