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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：
10096175
负责人：
JAKE JINKUN CHEN
金额：
$ 72.24万
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/10096175
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

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).

近50% 30岁以上的美国成年人患有牙周病（PD）。PD的基本病理