A Long Noncoding RNA Amerliorates Periodontitis via Distinct Epigenetic Pathways

长非编码 RNA 通过独特的表观遗传途径改善牙周炎

• 批准号: 10308042
• 负责人: JAKE JINKUN CHEN
• 金额: $ 69.91万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308042
• 关键词: Adenoviruses; Adult; Age; American; Antigen-Antibody Complex; Atherosclerosis; Binding Proteins; Biological; Biological Process; Biology; Blood; Bone Marrow; Bone Marrow Stem Cell; Bone Regeneration; Bone Resorption; Bone Tissue; Cardiovascular system; Cell Differentiation process; Cell Proliferation; Cells; Clinical; Clinical Trials; Code; Coin; Dental Clinics; Deterioration; Development; Diabetes Mellitus; Disease; Disease Progression; Elements; Endocrine system; Epigenetic Process; Etiology; FDA approved; Family; Foundations; Functional disorder; Gene Cluster; Gene Expression; Genes; Human Genome; Impairment; Inflammation; Inflammatory; Knockout Mice; Laboratories; Length; Link; Literature; MAP Kinase Gene; Malignant Neoplasms; Measurement; Measures; Metabolic; Modeling; Molecular; Molecular Biology; Mus; Neuraxis; Nucleotides; Oral Pathology; Osteoblasts; Osteoclasts; Osteogenesis; Outcome Study; Outcomes Research; Pathogenesis; Pathologic; Pathology; Pathway interactions; Pattern; Periodontal Diseases; Periodontitis; Pharmacology; Play; Preventive; Process; RNA; RNA Binding; Reproductive system; Research; Research Personnel; Research Project Grants; Role; Sampling; Signal Pathway; Stromal Cells; TLR4 gene; Techniques; Therapeutic; Therapeutic Agents; Therapeutic Effect; Tooth Diseases; Tooth Loss; Transcript; Untranslated RNA; Up-Regulation; adult stem cell; alveolar bone; base; bone; cell type; gain of function; gene therapy; genetic risk factor; human disease; induced pluripotent stem cell; insight; knockout gene; macrophage; microCT; microbiome analysis; mouse model; new therapeutic target; next generation; novel; novel therapeutics; osteoclastogenesis; osteogenic; overexpression; palliative; relating to nervous system; side effect; skills; stem cell differentiation; therapeutic evaluation; therapeutic target; therapeutically effective; transcription factor; transcriptome sequencing; translational study; virtual

Nearly 50% of American adults over age 30 have periodontal disease (PD). The basic pathology of PD is excessive alveolar bone resorption leading to tooth loss. Furthermore, PD can trigger general inflammation, adversely influencing cardiovascular, central nervous, reproductive and endocrine systems. Our laboratory has explored a variety of strategies for treating this disease and is still actively searching for a more effective and practical therapy with minimal side effects to cure the disease. Long noncoding RNAs (lncRNAs) are a family of non-protein-coding transcripts with the length longer than 200 nucleotides. LncRNAs participate in a wide repertoire of biological processes and play important roles in gene expression and posttranscriptional processes and are also implicated in the pathogenesis of many diseases. However, the functions of lncRNAs in dental diseases are just beginning to be uncovered. LncRNA ANRIL was the first shared genetic risk factor of atherosclerosis, PD, diabetes and cancers, thereby coined to APCD. Our laboratory has performed extensive preliminary studies including studies on lncRNA-APDC knockout mice. Our hypothesis is that lncR-APDC inhibits inflammation, osteoclastic bone resorption and promotes osteogenesis and alveolar bone regeneration through specific epigenetic pathways, by which efficiently targeting the pathophysiology of periodontitis. Aim 1 will determine the functions of lncR-APDC in periodontitis via loss- and gain-of-function approaches. Next generation RNA-Seq will be performed to elucidate the expression patterns of the participating genes and cellular pathways altered by the lncRNA dysregulation. Aim 2 will use state-of-the-art techniques to determine the cellular localization of lncR-APDC and decipher the mechanisms by characterizing the protein and RNA binding partners and chromosomal regions regulated by the lncR-APDC. Aim 3 will test the therapeutic effects of lncR- APDC in periodontitis to determine lncR-APDC’s effect on inflammation, osteoclastic bone resorption and alveolar bone regeneration. The results will provide a paradigm shift and advance the research field vertically in three ways. Firstly, we have initially found that lncR-APDC could play a pivotal role in cell differentiation and proliferation in PD. However, how this lncRNA is involved in PD progression is virtually unknown. Therefore, the results will reveal a novel pathological mechanism of PD deterioration and progression. Secondly, we will decipher the pathways of lncR-APDC modulating gene clusters in different cells playing active roles in the periodontal microenvironment and their roles in the PD progression, which will lead to the discovery of novel therapeutic targets. Finally, we will examine the potential utility of our newly constructed adenovirus conjugated lncR-APDC, as a safe and effective therapeutic measure for PD in dental clinics. An interdisciplinary team of investigators with complementary and synergistic skills will conduct the studies (Jake Chen – Experimental Oral Pathology and Bone Biology; Qisheng Tu – Cell and Molecular Biology; Thomas Van Dyke – Periodontology and RNA-Sequencing; Hans Johansson – RNA Biology and lncRNA FISH).

近 50% 30 岁以上的美国成年人患有牙周病 (PD)。 PD的基本病理学 过度的牙槽骨吸收导致牙齿脱落。此外，PD可引发全身炎症， 对心血管、中枢神经、生殖和内分泌系统产生不利影响。我们实验室有 探索了多种治疗该疾病的策略，并且仍在积极寻找更有效和更有效的方法。 副作用最小的实用疗法可以治愈疾病。长非编码 RNA (lncRNA) 是一个家族 长度超过200个核苷酸的非蛋白质编码转录本。 LncRNA 广泛参与 生物过程的全部内容，并在基因表达和转录后过程中发挥重要作用 并且还与许多疾病的发病机制有关。然而，lncRNA 在牙科中的功能 疾病才刚刚开始被发现。 LncRNA ANRIL 是第一个共享的遗传危险因素 动脉粥样硬化、PD、糖尿病和癌症，因此被称为 APCD。我们的实验室进行了广泛的 初步研究包括对 lncRNA-APDC 敲除小鼠的研究。我们的假设是 lncR-APDC 抑制炎症、破骨细胞骨吸收并促进成骨和牙槽骨再生 通过特定的表观遗传途径，有效地针对牙周炎的病理生理学。目标1 将通过功能丧失和功能获得方法确定 lncR-APDC 在牙周炎中的功能。下一个 将进行一代RNA-Seq以阐明参与基因和细胞的表达模式 lncRNA失调改变的通路。目标 2 将使用最先进的技术来确定 lncR-APDC 的细胞定位并通过表征蛋白质和 RNA 结合来破译其机制 伴侣和染色体区域受 lncR-APDC 调节。目标3将测试lncR-的治疗效果 APDC 在牙周炎中确定 lncR-APDC 对炎症、破骨细胞骨吸收和 牙槽骨再生。研究结果将提供范式转变并垂直推进研究领域 三种方式。首先，我们初步发现lncR-APDC在细胞分化和分化过程中发挥着关键作用。 PD 中的增殖。然而，这种 lncRNA 如何参与 PD 进展实际上尚不清楚。因此， 结果将揭示PD恶化和进展的新病理机制。其次，我们将 破译不同细胞中 lncR-APDC 调节基因簇的通路，在 牙周微环境及其在 PD 进展中的作用，这将导致新的发现 治疗目标。最后，我们将检查新构建的腺病毒缀合的潜在效用 lncR-APDC，作为牙科诊所治疗帕金森病的一种安全有效的治疗措施。跨学科团队 具有互补和协同技能的研究人员将进行研究（Jake Chen – 实验口头 病理学和骨生物学；涂启胜——细胞与分子生物学；托马斯·范·戴克 – 牙周病学 RNA测序； Hans Johansson – RNA 生物学和 lncRNA FISH）。