Date of Award

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Drug Discovery and Biomedical Sciences

College

College of Graduate Studies

First Advisor

Patrick M. Woster

Second Advisor

Craig C. Beeson

Third Advisor

Chad Novince

Fourth Advisor

Yuri Peterson

Fifth Advisor

Oziem Yilmaz

Abstract

Periodontal disease (PD) affects nearly half of the adult United States 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 studies outlined in this dissertation will exploit this crosstalk for the design of new potential therapies for PD. The central hypothesis of this dissertation 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. This hypothesis was tested through completion of the following Specific Aims: Specific Aim 1: To mechanistically define the role of KDM4B in periodontal inflammation; Specific Aim 2: To design a novel inhibitor of KDM4B for adjunctive treatment of PD inflammation, and Specific Aim 3: To evaluate novel and known KDM4B inhibitors for in vivo activity as anti-inflammatory agents. KDM4B inhibition prevented the A.a-induced immune response in vitro and in vivo. KDM4B inhibition also reduced osteoclast formation in vitro and bone loss in vivo. KDM4B activity is heightened in periodontal disease in clinical tissues as well as in murine calvarial tissue sections treated with A.a. KDM4B inhibition mediated immunosuppression relies on the concurrent overactivation of KDM1A. Computational chemical screens identified several hit scaffolds, one of which was optimized using phenotypic screen guided binary QSAR. From an extensive in silico derivative library, 25 novel derivatives were synthesized, 8 of which caused significant immunosuppression.

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