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 MEG 3 -4总结 革兰氏阴性菌是引起高发病率和死亡率的重要人类病原体， 并且它们不断增加的抗生素耐药性对医疗保健提出了严峻的挑战。 此外，异常的宿主防御，包括过度的炎症反应， 感染后的有害影响，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;然而，其 对细菌感染的炎症反应中的功能知之甚少。我们使用了 筛选方法鉴定lncRNA MEG 3 -4作为组织特异性调节剂， 肺部细菌感染时的炎症反应。我们还发现了一个新的角色 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，MEG 3 -4作为一种免疫调节剂发挥作用。 竞争性内源性RNA，其结合miR-138并释放miRNA的靶标IL-1 β 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 这些发现促使我们进一步剖析lncRNA在抗- 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脓毒症模型。我们假设 MEG 3 -4的下调将通过缓和炎症反应来减轻Pa感染。到 为了验证这一假设，我们提出了以下三个具体目标：1，确定MEG 3的作用- 4、在宿主防御细菌感染中具有组织特异性; MEG 3 -4调节炎症反应的分子机制 3.为了确定在关键细胞群中MEG 3 -4的抑制是否会 舒缓炎症并帮助控制感染。这项研究的完成将极大地 扩大我们对lncRNA的作用和相关调节途径的了解，这 将有利于制药界在他们绝望地寻找新的细菌， 针对多药耐药菌株的治疗剂。

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