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（PD）。帕金森病的基本病理 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。本实验室 探索了治疗这种疾病的各种策略，并仍在积极寻找更有效， 以最小的副作用来治愈疾病的实用疗法。长链非编码RNA（lncRNA）是一类 长度超过200个核苷酸的非蛋白质编码转录物。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 并且还涉及许多疾病的发病机理。然而，lncRNA在牙本质中的功能， 疾病才刚刚开始被发现。LncRNA ANRIL是第一个共享的遗传风险因素， 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。我们假设lncR-APDC 抑制炎症、骨吸收、促进骨生成和牙槽骨再生 通过特定的表观遗传途径，有效地靶向牙周炎的病理生理学。要求1 将通过功能丧失和获得方法确定lncR-APDC在牙周炎中的功能。下 将进行第二代RNA-Seq以阐明参与基因和细胞的表达模式。 通过lncRNA失调改变的途径。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结合来破译机制 由lncR-APDC调控的伴侣和染色体区域。目的3将测试lncR的治疗效果- 牙周炎中的APDC，以确定lncR-APDC对炎症、骨质疏松性骨吸收和 牙槽骨再生研究结果将提供一种范式转变，并在垂直方向上推进研究领域。 三种方式。首先，我们初步发现lncR-APDC在细胞分化中起关键作用， 在PD中增殖。然而，这种lncRNA如何参与PD进展几乎是未知的。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调节基因簇在细胞凋亡中发挥积极作用的途径， 牙周微环境及其在PD进展中的作用，这将导致发现新的 治疗目标最后，我们将研究我们新构建的腺病毒结合的潜在效用， lncR-APDC是一种安全有效的治疗PD的方法。的跨学科团队 具有互补和协同技能的研究人员将进行研究（Jake Chen-实验口语 病理学和骨生物学; Qisheng Tu-细胞和分子生物学;托马斯货车Dyke-牙周病学 和RNA测序; Hans Johansson-RNA Biology and lncRNA FISH）。