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%的30岁以上的美国成年人患有牙周病。帕金森病的基本病理 牙槽骨过度吸收会导致牙齿脱落。此外，帕金森病可引发全身炎症， 对心血管、中枢神经、生殖和内分泌系统产生不利影响。我们的实验室有 探索了治疗这种疾病的各种策略，并仍在积极寻找更有效和 以最小的副作用治愈这种疾病的实用疗法。长非编码RNA(LncRNAs)是一类 长度超过200个核苷酸的非蛋白质编码转录本。LncRNA参与了广泛的 在基因表达和转录后过程中发挥重要作用的生物过程 而且还与许多疾病的发病机制有关。然而，lncRNAs在牙科中的功能 疾病才刚刚开始被发现。LncRNA ANRIL是第一个共同的遗传风险因素 动脉粥样硬化、帕金森病、糖尿病和癌症，从而催生了APCD。我们的实验室已经进行了广泛的实验 初步研究包括对lncRNA-apdc基因敲除小鼠的研究。我们的假设是INCNR-APDC 抑制炎症、破骨细胞性骨吸收，促进成骨和牙槽骨再生 通过特定的表观遗传途径，有效地靶向牙周炎的病理生理。目标1 将通过功能丧失和功能获得的方法确定LncR-APDC在牙周炎中的功能。下一首 将进行代RNA-Seq以阐明参与基因和细胞的表达模式 被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的细胞定位及其与蛋白质和RNA结合的机制 伙伴和受LncR-APDC调控的染色体区域。目标3将测试lncr的治疗效果- APDC在牙周炎中的应用研究LncR-APDC对炎症、破骨细胞性骨吸收和牙周炎的影响 牙槽骨再生。研究结果将提供范式转换，并在#年垂直推进研究领域 三种方式。首先，我们初步发现LncR-APDC可能在细胞分化和分化中发挥关键作用。 帕金森病的细胞增殖。然而，这种lncRNA如何参与帕金森病的进展几乎是未知的。因此， 这些结果将揭示帕金森病恶化和进展的新的病理机制。其次，我们将 破译LncR-APDC在不同细胞中发挥积极作用的基因簇调控途径 牙周微环境及其在帕金森病进展中的作用 治疗靶点。最后，我们将检验我们新构建的偶联腺病毒的潜在用途。 LncR-APDC作为一种安全有效的牙科门诊帕金森病治疗措施。一支跨学科的团队 具有互补和协同技能的研究人员将进行研究(杰克·陈-实验口头 病理学与骨生物学；齐生屠呦呦细胞与分子生物学；托马斯·范·戴克-牙周学 和RNA测序；Hans Johansson-RNA生物学和IncRNA FISH)。