Validation and Development of KDM4B Inhibitors to Target Peridontal Disease

项目总结/摘要 牙周病影响近一半的美国成年人口，其特征是细菌性- 导致炎性骨丢失。传统和新兴的牙周炎治疗方法不 通常靶向宿主免疫应答，这是组织损伤的主要来源。去甲基化 赖氨酸特异性脱甲基酶1（KDM 1A）在组蛋白3赖氨酸4处的活性导致促炎性细胞因子的减少。 细胞因子转录相比之下，赖氨酸特异性脱甲基酶4 B（KDM 4 B）是组蛋白脱甲基酶， 特异性去甲基化组蛋白3三甲基赖氨酸9（H3 K9 me 3）。有趣的是，此前的数据显示， 这两种酶之间的相互作用导致平衡的系统，其中赖氨酸9甲基化作为一种酶， 赖氨酸4通过KDM 1A去甲基化的先决条件。本提案中概述的研究计划将利用这一点 串扰的设计新的潜在的治疗PD。这一提议的核心假设是， 通过引入特异性KDM 4 B抑制剂来促进KDM 1A活性将通过控制PD来减轻PD。 免疫系统过度活跃，使宿主能够更好地控制疾病， 复发（图1）。我们将通过完成以下具体目标来检验这一假设： 1：从机制上定义KDM 4 B在牙周炎症中的作用;具体目标2：使用基于结构的 设计技术以发现新的KDM 4 B抑制剂，用于PD炎症的连续治疗，以及 具体目标3：评价新型和已知KDM 4 B抑制剂的体内免疫调节活性。我们 初步数据显示，抑制KDM 4 B导致促炎性细胞因子的显著降低， 细胞因子转录和翻译。现有的药物将用于进一步验证KDM 4 B作为PD的靶点， 随后是计算化学对接实验与物理化合物筛选配对， 化合物结构与疾病进展标志物变化之间的相关性。这些新颖 将在体外和体内研究化合物的功效和毒性。这项研究将提供更多 对表观遗传机制的深入了解可能在牙周病中发挥重要作用 进展，验证KDM 4 B作为牙周炎的药物靶点，并导致开发新的治疗药物 用于牙周炎的局部免疫调节辅助治疗。该研究金将提供以下培训： 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 口腔健康学术临床医生/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.