Long noncoding RNAs interact with miRNAs to regulate inflammatory response

长非编码 RNA 与 miRNA 相互作用调节炎症反应

• 批准号: 10216960
• 负责人: Colin K Combs
• 金额: $ 34.75万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216960
• 关键词: Alveolar Macrophages; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibiotic Resistance; Bacteria; Bacterial Infections; Binding; Bioinformatics; Cell physiology; Cells; Cellular biology; Clinical; Communicable Diseases; Communities; Competitive Binding; Data; Development; Disease Progression; Down-Regulation; Drug Targeting; Epigenetic Process; Feasibility Studies; Gene Expression; Genes; Goals; Gram-Negative Bacteria; Healthcare; High-Throughput Nucleotide Sequencing; Host Defense; Immune response; Immune system; Immunity; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Intervention; Klebsiella pneumoniae; Knowledge; Lung; Lymphoid Cell; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Biology; Molecular Cloning; Morbidity - disease rate; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mus; Organ; Outcome; Pharmacologic Substance; Phenotype; Play; Population; Preventive measure; Protein Isoforms; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; RNA; RNA Binding; Refractory; Regulation; Regulator Genes; Regulatory Pathway; Repression; Research; Resolution; Role; Sepsis; Solid; Techniques; Testing; Therapeutic; Tissues; Transcript; Untranslated RNA; Up-Regulation; Work; cell growth; chromatin remodeling; clinical application; design; drug development; effective therapy; experience; gene repression; human pathogen; improved; in vivo imaging; innovation; lung injury; mortality; new therapeutic target; novel; organ growth; pathogen; resistant strain; screening; therapeutic target

Summary for lncR MEG3-4 Gram-negative bacteria are important human pathogens that cause high morbidity and mortality, and their increasing antibiotic resistance presents daunting challenges to healthcare. Furthermore, aberrant host defense including excessive inflammatory responses causes detrimental effects following infection, resulting in uncontrollable sepsis and severe outcomes. Long noncoding RNAs (lncRNAs) are important regulators of gene expression; however, their functions in inflammatory responses to bacterial infection are poorly understood. We used a screening approach to identify the lncRNA MEG3-4 as a tissue-specific modulator of inflammatory responses during pulmonary bacterial infection. We also discovered a novel role for microRNA-138 in regulating inflammation through a critical interaction with the lncRNA MEG3-4. Importantly, we revealed a novel mechanism by which MEG3-4 functions as a competing endogenous RNA that binds miR-138 and releases the miRNA's target, IL-1 mRNA. This in turn intensified the inflammatory responses in both cells and mice. These exciting findings prompted us to further dissect the decoy modulation mechanism of lncRNAs in anti- bacterial immunity, as well as assess the impact on phenotype and disease progression in a sepsis model following Pseudomonas aeruginosa infection. We hypothesize that downregulation of MEG3-4 will mitigate Pa infection by soothing the inflammatory response. To test this hypothesis, we propose the following three specific aims: 1, To define the role of MEG3- 4 in host defense against bacterial infection in a tissue-specific manner; 2, To study the molecular mechanisms by which MEG3-4 regulates the inflammatory response against infection; and 3, To determine whether repression of MEG3-4 in critical cell populations will soothe inflammation and help control infection. Completion of this research will dramatically expand our knowledge of the role of lncRNAs and the associated regulatory pathways, which will benefit the pharmaceutical community in their desparate search for new bacterial therapeutics against multidrug resistant strains.

InncR MEG3-4摘要 革兰氏阴性菌是导致高发病率和死亡率的重要人类病原体， 他们日益增长的抗生素耐药性给医疗保健带来了令人生畏的挑战。 此外，包括过度炎症反应在内的异常宿主防御是导致 感染后的不利影响，导致无法控制的脓毒症和严重的后果。 长非编码RNA(LncRNAs)是基因表达的重要调节因子；然而，它们的 对细菌感染的炎症反应中的功能知之甚少。我们使用了一个 鉴定lncRNA MEG3-4为组织特异性调节因子的筛选方法 肺部细菌感染时的炎症反应。我们还发现了一个新的角色 对于microRNA-138通过与lncRNA的关键相互作用调节炎症 MEG3-4。重要的是，我们揭示了一种新的机制，MEG3-4通过它作为一种 竞争的内源核糖核酸结合miR-138并释放miRNA的靶标IL-1miRNA。 这反过来加剧了细胞和小鼠的炎症反应。这些令人兴奋的东西 这些发现促使我们进一步剖析了lncRNAs在反转录病毒中的诱骗调控机制 细菌免疫，以及评估对表型和疾病进展的影响 铜绿假单胞菌感染后的脓毒症模型。我们假设 下调MEG3-4将通过缓解炎症反应来减轻PA感染。至 为了验证这一假说，我们提出了以下三个具体目标：1、定义MEG3的作用- 4以组织特异性的方式防御宿主的细菌感染；2，研究 MEG3-4调节炎症反应的分子机制 感染；以及3，确定关键细胞群中抑制MEG3-4是否会 舒缓炎症，帮助控制感染。这项研究的完成将极大地 扩大我们对LncRNAs的作用和相关调控途径的知识，这些途径 将使制药行业在单独寻找新细菌时受益 针对多重耐药菌株的治疗。

项目成果

Methods for studying toxicity of silica-based nanomaterials to living cells.

研究二氧化硅基纳米材料对活细胞毒性的方法。

• DOI: 10.1007/978-1-62703-468-5_15
• 发表时间: 2013
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Zhao,Yang;Jin,Yuhui;Hanson,Aaron;Wu,Min;Zhao,JuliaXiaojun
• 通讯作者: Zhao,JuliaXiaojun

CRISPR-Cas systems target endogenous genes to impact bacterial physiology and alter mammalian immune responses.

• DOI: 10.1186/s43556-022-00084-1
• 发表时间: 2022-07-20
• 期刊: Molecular biomedicine
• 影响因子: 4

Degradable antimicrobial polycarbonates with unexpected activity and selectivity for treating multidrug-resistant Klebsiella pneumoniae lung infection in mice.

• DOI: 10.1016/j.actbio.2019.05.057
• 发表时间: 2019-05
• 期刊: Acta biomaterialia
• 影响因子: 9.7
• 作者: Chuan Yang;Weiyang Lou;Guansheng Zhong;Ashlynn L. Z. Lee;Jiayu Leong;Willy Chin;Bisha Ding;C. Bao;J. Tan;Qinqin Pu;Shujun Gao;Liang Xu;L. Hsu;Min Wu;J. Hedrick;W. Fan;Yi Yan Yang

Applications and challenges of CRISPR-Cas gene-editing to disease treatment in clinics.

• DOI: 10.1093/pcmedi/pbab014
• 发表时间: 2021-09
• 期刊: Precision clinical medicine
• 影响因子: 5.3
• 作者: Liu W;Li L;Jiang J;Wu M;Lin P
• 通讯作者: Lin P