Potentials of Epigenetic Molecules in Attenuating the Phenotypes of Periodontitis

表观遗传分子减轻牙周炎表型的潜力

• 批准号: 10736171
• 负责人: JAKE JINKUN CHEN
• 金额: $ 69.23万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736171
• 关键词: 3' Untranslated Regions; Adult; Affinity; Age; Alveolar Bone Loss; American; Area; Binding; Biocompatible Materials; Biological; Biology; Bone Marrow; Bone Regeneration; Bone Resorption; Bromodomain; Bromodomains and extra-terminal domain inhibitor; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Cellular biology; Clinic; Clinical Trials; Crossbreeding; Disease; Disease Progression; Dose; Drug Delivery Systems; Drug Kinetics; Endogenous Factors; Epigenetic Process; Etiology; Experimental Pathology; Foundations; Functional disorder; Gene Deletion; Gene Expression; Genes; Genetic Transcription; Goals; Immune Complex Diseases; Immunology; Individual; Inflammation; Inflammatory; Inflammatory Response; Injections; Investigation; Knockout Mice; Knowledge; Laboratories; Macrophage; Massachusetts; Measurement; Mediating; MicroRNAs; Modeling; Modification; Molecular; Molecular Biology; Mus; Natural regeneration; Osteoblasts; Osteoclasts; Osteogenesis; Outcome Measure; Palliative Care; Pathogenesis; Pathologic; Pathway interactions; Patients; Periodontal Diseases; Periodontitis; Periodontium; Pharmacodynamics; Phenotype; Population; Protein Inhibition; Regulator Genes; Reporting; Resistance; Ribosomal DNA; Rodent; Role; Severity of illness; Signal Pathway; Signal Transduction; Site; Stromal Cells; Structure; System; Technology; Tertiary Protein Structure; Therapeutic; Therapeutic Agents; Time; Tissues; Tooth Loss; Tooth structure; Transgenic Mice; Treatment Efficacy; Untranslated RNA; alveolar bone; beta catenin; bone; bone mass; cell type; cytokine; cytotoxicity; design; epigenetic therapy; experience; familial amyotrophic lateral sclerosis; gene therapy; genetic element; genetic manipulation; healing; human disease; induced pluripotent stem cell; inhibitor; innovation; invention; mouse model; nano; nanomaterials; nanoparticle; novel; novel therapeutics; osteoclastogenesis; overexpression; regenerative; single-cell RNA sequencing; skills; therapeutic gene; tissue regeneration; transcription factor; transcriptomics; translational study

Periodontal disease represents one of the most prevalent diseases in adult population as 47% of Americans over age 30 have the disease. Periodontitis is a complex immune and inflammatory disease, characterized by three major pathological features: exacerbating inflammatory response, excess osteoclastic alveolar bone resorption and decreased osteoblastic bone formation. Unfortunately, there are only palliative treatments in clinics currently. Our laboratory has explored a variety of strategies to ameliorate the severity of the disease including application of bone marrow stromal cells (BMSCs) and induced pluripotent stem cells (iPSCs) with major transcription factors, such as Runx2, Osx and SATB2 in cell-based gene-therapy, but at the meantime experienced drawbacks and limitations of these approaches. Therefore, we are actively searching for a new therapy that blocks the major pathogenetic elements and stimulates endogenous factors to regenerate the tissues lost in periodontitis. Epigenetic molecules have recently emerged as potent regulators of gene expression and therapeutic agents for a variety of human diseases. We for the first time found that the novel synthetic BET protein inhibitor, JQ1, specifically inhibits periodontal inflammation and significantly reduces alveolar bone loss in murine periodontitis model. Additionally, we are the first to identify miR-335-5p and characterized its role in promoting bone formation and regeneration. Overexpressing miR-335-5p ameliorates tissue damage in experimental periodontitis which further provides a foundation and a strong premise for the current proposal. In this proposal we will use an elegantly designed and precisely synthesized nanoparticle (NP) system that will carry both JQ1 and miR-335-5p and specifically release them into major target cells in periodontitis, resulting in a block of the pathogenesis and activation of endogenous regenerative factors. In Aim 1, we will delineate the molecular mechanisms of miR-335-5p effects in periodontitis under gene deficient and overexpressing conditions using our newly generated genetically manipulated rodents. In Aim 2, we will define the epigenetic effects of nanoparticle-mediated precision and specific delivery of JQ1 and miR-335-5p on their corresponding target cells. In Aim 3, we will determine the therapeutic efficacy of combined application of epi-modulators in a mouse model of periodontitis. We will deliver the epi- biological nano-products simultaneously, individually, or alternatingly to assess the therapeutic impact at different disease stages. Outcome measures will include unbiased single cell RNA-sequencing, 16S rDNA profiling, qualitative and quantitative periodontal analyses and pharmacokinetics. Using innovative epigenetic approaches to understand the pathophysiology of periodontal disease and its therapeutic potentials is a paradigm shift. This investigation will be conducted by an interdisciplinary team composed of the PI and three C-Is who have profound knowledge and complementary skills in the following areas: Experimental Pathology and Bone Biology; Cell and Molecular Biology; Inflammation and Immunology, and Biomaterials and Drug Delivery.

牙周病是成年人中最常见的疾病之一，占成年人口的 47% 30岁以上的美国人都患有这种疾病。牙周炎是一种复杂的免疫和炎症性疾病， 具有三大病理特征：炎症反应加剧、炎症反应过度 破骨细胞牙槽骨吸收和成骨细胞骨形成减少。不幸的是，有 目前在临床上仅是姑息治疗。我们的实验室探索了多种策略来改善 疾病的严重程度，包括骨髓基质细胞（BMSC）和诱导多能细胞的应用 具有主要转录因子的干细胞 (iPSC)，例如基于细胞的基因治疗中的 Runx2、Osx 和 SATB2， 但同时也经历了这些方法的缺点和局限性。因此，我们正在积极 寻找一种新的疗法来阻断主要致病因素并刺激内源性因素 再生牙周炎中损失的组织。表观遗传分子最近已成为有效的调节剂 多种人类疾病的基因表达和治疗剂。我们第一次发现 新型合成BET蛋白抑制剂JQ1，特异性抑制牙周炎症，并显着 减少小鼠牙周炎模型中的牙槽骨丢失。此外，我们是第一个鉴定出 miR-335-5p 并表征了其在促进骨形成和再生中的作用。过表达 miR-335-5p 改善实验性牙周炎中的组织损伤，这进一步提供了基础和强大的 当前提案的前提。在这个提案中，我们将使用一个精心设计和精确合成的 纳米颗粒 (NP) 系统将携带 JQ1 和 miR-335-5p 并将它们特异性释放到主要靶标中 牙周炎中的细胞，导致内源性再生因子的发病机制和激活受阻。 在目标 1 中，我们将描述 miR-335-5p 在基因作用下对牙周炎影响的分子机制。 使用我们新产生的基因操纵啮齿动物来检测缺陷和过度表达的情况。瞄准 2，我们将定义纳米颗粒介导的JQ1精确性和特异性递送的表观遗传效应 和 miR-335-5p 在其相应的靶细胞上。在目标 3 中，我们将确定治疗效果 表观调节剂在牙周炎小鼠模型中的联合应用。我们将交付 Epi- 同时、单独或交替地评估生物纳米产品在不同条件下的治疗效果 疾病阶段。结果测量将包括公正的单细胞 RNA 测序、16S rDNA 分析、 定性和定量牙周分析和药代动力学。使用创新的表观遗传学方法 了解牙周病的病理生理学及其治疗潜力是一个范式转变。 这项调查将由一个跨学科团队进行，该团队由 PI 和三名 C-I 组成。 在以下领域拥有深厚的知识和互补的技能：实验病理学和骨 生物学;细胞与分子生物学；炎症与免疫学、生物材料和药物输送。