Validation and Development of KDM4B Inhibitors to Target Peridontal Disease

项目摘要/摘要 牙周病影响着近一半的美国成年人口，其特点是细菌- 导致炎症性骨丢失。传统和新兴的牙周炎治疗方法不能 通常以宿主免疫反应为目标，这是组织损伤的主要来源。去甲基化 赖氨酸特异性去甲基酶1(KDM1A)在组蛋白3赖氨酸4处的活性导致促炎作用的减少 细胞因子转录。相反，赖氨酸特异性去甲基酶4B(KDM4B)是一种组蛋白去甲基酶 特指去甲基化组蛋白3三甲基赖氨酸9(H3K9me3)。有趣的是，之前的数据显示 这两种酶之间的串扰导致了一个平衡的系统，其中赖氨酸9甲基化作为一种 KDM1a对赖氨酸4去甲基化的先决条件。这项提案中概述的研究计划将利用这一点 帕金森病潜在新疗法设计的串扰。这项提议的中心假设是 通过引入特定的KDM4B抑制剂来促进KDM1A的活性将通过控制 疾病区域的过度活跃的免疫系统，使宿主能够更好地管理疾病并预防其 复发(图1)。我们将通过完成以下具体目标来检验这一假设：具体目标 1：机械地确定KDM4B在牙周炎中的作用；具体目标2：使用基于结构的 设计技术以发现KDM4B的新抑制剂用于辅助治疗帕金森病炎症，以及 具体目标3：评估新的和已知的KDM4B抑制剂在体内的免疫调节活性。我们的 初步数据显示，抑制KDM4B导致促炎因子显著减少 细胞因子转录和翻译。现有的药物将被用来进一步验证KDM4B作为PD的靶点， 然后是计算化学对接实验与物理化合物屏幕配对来描绘 化合物结构与疾病进展标记物变化的相关性。这些小说 化合物将在体外和体内进行有效性和毒性的测试。这项研究将提供更多的 对牙周病的表观遗传学机制的深入了解可能会对牙周病起到重要作用 进展，验证KDM4B作为牙周炎的药物靶点，并导致开发一种新的治疗方法 用于牙周炎的局部免疫调节辅助治疗。该奖学金将在以下方面提供培训 免疫学和药物设计，并将促进学员发展成为一个独特的和迫切需要的 口腔健康学院临床医生/科学家。

Project Summary/Abstract 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.