Periodontal disease affects nearly half of the adult American population and is characterized by bacterial- driven inflammatory bone loss. Traditional and emerging treatments for periodontitis management do not typically target the host immune response, which is the major source of tissue damage. The demethylation activity of lysine-specific demethylase 1 (KDM1A) at histone 3 lysine 4 leads to a decrease in pro-inflammatory cytokine transcription. By contrast, lysine specific demethylase 4B (KDM4B) is a histone demethylase that specifically demethylates histone 3 trimethyllysine 9 (H3K9me3). Interestingly, previous data has shown that cross talk between these two enzymes leads to a balanced system wherein lysine 9 methylation serves as a prerequisite to lysine 4 demethylation by KDM1A. The research plan outlined in this proposal will exploit this crosstalk for the design of new potential therapies for PD. The central hypothesis of this proposal is that promotion of KDM1A activity by introduction of a specific KDM4B inhibitor will alleviate PD by controlling the overactive immune system in diseased areas, enabling the host to better manage the disease and prevent its recurrence (Fig.1). We will test this hypothesis through completion of the following Specific Aims:
Specific Aim 1 : Mechanistically define the role of KDM4B in periodontal inflammation;
Specific Aim 2 : Use structure-based design techniques to discover novel inhibitors of KDM4B for adjunctive treatment of PD inflammation, and Specific Aim 3: Evaluate novel and known KDM4B inhibitors for immunomodulatory activity in vivo. Our preliminary data have shown that inhibition of KDM4B results in significant decreases in pro-inflammatory cytokine transcription and translation. Existing drugs will be used to further validate KDM4B as a target for PD, followed by computational chemistry docking experiments paired with physical compound screens to delineate the correlations between compound structure and changes in disease progression markers. These novel compounds will be interrogated both in vitro and in vivo for efficacy and toxicity. This study will provide a more robust understanding of epigenetic mechanisms of that may play a significant role periodontal disease progression, validate KDM4B as a drug target for periodontitis, and result in development of a novel therapeutic for local immunomodulatory adjuvant treatment of periodontitis. This fellowship will provide training in immunology and drug design and will foster the development of the trainee into a unique and critically needed oral health academic clinician/scientist.
Periodontal disease affects 46% of the adult American population with limited effective adjunctive treatment options following traditional non-surgical or surgical therapies. The epigenetic mechanisms that govern periodontal health and disease are not well defined or understood. This research will result in the development of novel therapeutics that target major epigenetic mechanisms engaged in periodontal disease progression.
|Kirkpatrick, Joy E; Kirkwood, Keith L; Woster, Patrick M (2018) Inhibition of the histone demethylase KDM4B leads to activation of KDM1A, attenuates bacterial-induced pro-inflammatory cytokine release, and reduces osteoclastogenesis. Epigenetics 13:557-572|