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.

lncR MEG3-4 摘要 革兰氏阴性菌是重要的人类病原体，导致高发病率和死亡率， 它们日益增强的抗生素耐药性给医疗保健带来了严峻的挑战。 此外，异常的宿主防御，包括过度的炎症反应，会导致 感染后的不良影响，导致无法控制的败血症和严重后果。 长链非编码 RNA (lncRNA) 是基因表达的重要调节因子； 我们对细菌感染炎症反应的功能知之甚少。 筛选方法鉴定 lncRNA MEG3-4 作为组织特异性调节剂 我们还发现了肺部细菌感染期间的炎症反应。 microRNA-138 通过与 lncRNA 的关键相互作用调节炎症 重要的是，我们揭示了 MEG3-4 发挥作用的新机制。 竞争性内源性 RNA 结合 miR-138 并释放 miRNA 的靶标 IL-1 mRNA。 这反过来又加剧了细胞和小鼠的炎症反应，这些令人兴奋。 研究结果促使我们进一步剖析 lncRNA 在抗肿瘤中的诱饵调节机制 细菌免疫力，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。 MEG3-4 的下调将通过缓解炎症反应来减轻 Pa 感染。 为了检验这一假设，我们提出以下三个具体目标： 1、定义MEG3-的作用 4 宿主以组织特异性方式防御细菌感染； 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 MEG3-4 的抑制是否会影响 这项研究的完成将极大地缓解炎症并帮助控制感染。 扩大我们对 lncRNA 作用和相关调控途径的了解， 将有利于制药界拼命寻找新细菌 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