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

基本信息

批准号：
10526289
负责人：
JAKE JINKUN CHEN
金额：
$ 70.62万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
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/10526289
关键词：
Adenoviruses Adult Age American Atherosclerosis Binding Proteins Biological Biological Process Biology Blood Bone Marrow Stem Cell Bone Regeneration Bone Resorption Bone Tissue Cardiovascular system Cell Differentiation process Cell Proliferation Cells Cellular biology Central Nervous System Clinical Clinical Trials Code Coin Dental Clinics Deterioration Development Diabetes Mellitus Disease Disease Progression Elements Endocrine system Epigenetic Process Etiology FDA approved Family Fishes Foundations Functional disorder Gene Cluster Gene Expression Genes Human Genome Immune Complex Diseases Impairment Inflammation Inflammatory Knockout Mice Laboratories Length Link Literature MAP Kinase Gene Macrophage Malignant Neoplasms Measurement Measures Metabolic Modeling Molecular Molecular Biology Mus Nucleotides Oral Pathology Osteoblasts Osteoclasts Osteogenesis Outcome Study Outcomes Research Pathogenesis Pathologic Pathology Pathway interactions Pattern Periodontal Diseases Periodontitis Play Preventive Qualifying 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 Transcription Process Untranslated RNA Up-Regulation adult stem cell alveolar bone bone cell type gain of function gene therapy genetic risk factor human disease induced pluripotent stem cell insight knockout gene loss of function microCT microbiome analysis mouse model neural new therapeutic target next generation novel novel therapeutics osteoclastogenesis osteogenic overexpression palliative pharmacologic posttranscriptional side effect skills stem cell differentiation therapeutic evaluation therapeutic target therapeutically effective transcription factor transcriptome sequencing translational study virtual

项目摘要

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).

30岁以上的美国成年人中，近50％患有牙周疾病（PD）。 PD的基本病理是肺泡骨的过度分辨率，导致牙齿脱落。此外，PD可以触发一般炎症，不利影响心血管，中枢神经，生殖和内分泌系统。我们的实验室有探索了各种治疗这种疾病的策略，并且仍在积极寻找更有效的策略实际疗法具有最小的副作用以治愈疾病。长的非编码RNA（lncrnas）是一个家庭长度长于200个核苷酸的非蛋白质编码转录本。 lncrnas参加生物过程的曲目，并在基因表达和转录后过程中起重要作用并且在许多疾病的发病机理中也实施。但是，LNCRNA在牙齿中的功能疾病刚刚开始被发现。 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，从而归因于APCD。我们的实验室已经进行了广泛的表现初步研究，包括对LNCRNA-APDC敲除小鼠的研究。我们的假设是LNCR-APDC 抑制感染，破骨骨骨分辨率并促进成骨和肺泡骨再生通过特定的表观遗传途径，通过该途径有效地靶向牙周炎的病理生理。目标1 将通过丧失和功能获得的方法来确定LNCR-APDC在牙周炎中的功能。下一个将进行生成RNA-Seq以阐明参与基因和细胞的表达模式 LNCRNA失调改变的途径。 AIM 2将使用最先进的技术来确定通过表征蛋白质和RNA结合，LNCR-APDC的细胞定位并破译机制由LNCR-APDC调节的合作伙伴和染色体区域。 AIM 3将测试LNCR-的治疗作用牙周炎的APDC确定LNCR-APDC对炎症，整骨骨骼的影响和肺泡骨再生。结果将提供范式转移并垂直推进研究领域三种方式。首先，我们最初发现LNCR-APDC可以在细胞分化和 Pd中的增殖。但是，该LNCRNA如何参与PD进程是未知的。因此，结果将揭示PD确定和进展的新型病理机制。其次，我们会的破译LNCR-APDC调节基因簇的途径在不同细胞中起着活性作用的基因簇牙周微环境及其在PD进展中的作用，这将导致新颖的发现治疗靶标。最后，我们将研究新建的腺病毒结合的潜在效用 LNCR-APDC，作为牙科诊所中PD的安全有效治疗方法。一个跨学科团队具有完整和协同技能的研究人员将进行研究（杰克·陈（Jake Chen） - 实验性口头病理学和骨生物学； Qisheng tu - 细胞和分子生物学；托马斯·范·戴克（Thomas van Dyke） - 期次学和RNA测序；汉斯·约翰逊（Hans Johansson） - RNA生物学和lncrna鱼）。