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Novel role for protein kinase D in airway inflammation and antiviral immunity

蛋白激酶 D 在气道炎症和抗病毒免疫中的新作用

基本信息

批准号：
10576337
负责人：
Steve N Georas
金额：
$ 38.5万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2020-03-13 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576337
关键词：
Actins Attenuated CCR CXCL1 gene Cells Chemotactic Factors Complex Cytokine Gene Cytoskeleton Double-Stranded RNA Epithelial Cells Epithelium Functional disorder Gene Expression Genes Genetic Transcription Immune response Immune system Immunity In Vitro Infection Inflammation Influenza Influenza A virus Inhalation Innate Immune Response Interferons Knockout Mice Link Lung MAP3K7 gene Mediating Modeling Morbidity - disease rate Mus NF-kappa B Natural Immunity Neutrophil Infiltration Pattern recognition receptor Phosphorylation Protein Dephosphorylation Protein Isoforms Protein-Serine-Threonine Kinases Proteins Pulmonary Inflammation Role Signal Pathway Signal Transduction Signal Transduction Induction Small Interfering RNA TBK1 gene TLR3 gene Testing Tight Junctions Tretinoin Viral Virus Virus Diseases Virus Replication airway epithelium airway inflammation antagonist antiviral immunity cell motility chemokine chemokine receptor cofilin conditional knockout cytokine helicase in vivo influenza infection influenza pneumonia inhibitor interstitial knock-down lung injury melanoma migration mortality neutrophil novel protein kinase D respiratory virus sensor transcription factor

项目摘要

Respiratory viruses are a major cause of morbidity and mortality worldwide. After infecting their target cells, viruses are sensed by different pattern recognition receptors (PRR’s) that initiate innate anti-viral immune responses. Viral double stranded RNA (dsRNA) is a potent stimulator of innate immunity and activates toll-like receptor 3 (TLR3) as well as the intracellular helicases RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated protein 5). Double stranded RNA sensors are expressed by the airway epithelium, and couple to complex downstream signaling pathways that initiate the expression of interferons and cytokine genes, resulting in airway inflammation and induction of anti-viral immunity. This R01 application is based on our serendipitous discovery that the serine/threonine kinase protein kinase D (PKD) has a previously overlooked role in innate immune responses driven by the dsRNA polyI:C. There are three PKD isoforms (PKD1-3), but little is known about their expression or function in the lung. Using targeted siRNA knock-down and a new line of knock-out mice, we found that polyI:C-induced epithelial cytokine gene expression and neutrophil recruitment to the lung are both dependent on PKD3. This appears to involve a previously unreported role for PKD3 in polyI:C signaling in epithelial cells, as well as in chemokine receptor signal transduction in neutrophils. Excitingly, we also discovered that a potent and selective PKD antagonist protects mice from infection with influenza A virus (IAV). In this revised R01 application, we propose three Aims that will: explain exactly how PKD mediates dsRNA signal transduction in airway epithelial cells (Aim 1), use conditional deletion and other strategies to unravel a new neutrophil specific role for PKD3 in lung inflammation (Aim 2), and test the hypothesis that targeting PKD will attenuate lung inflammation after influenza infection in mice (Aim 3).

呼吸道病毒是世界范围内发病和死亡的主要原因。在感染了他们的目标之后在细胞中，病毒被不同的模式识别受体（PRR）感知，这些受体启动先天性抗病毒免疫反应。病毒双链RNA（dsRNA）是先天免疫的有效刺激物，激活Toll样受体3（TLR 3）以及细胞内解旋酶RIG-I（视黄酸诱导的基因I）和MDA 5（黑素瘤分化相关蛋白5）。双链RNA传感器由气道上皮细胞表达，并与复杂的下游信号通路偶联，启动干扰素和细胞因子基因的表达，导致气道炎症，诱导抗病毒免疫。这个R 01应用程序是基于我们的偶然发现，丝氨酸/苏氨酸激酶蛋白激酶D（PKD）在先天性免疫中具有以前被忽视的作用，由dsRNA polyI：C驱动的反应。有三种PKD亚型（PKD 1 -3），但知之甚少它们在肺中的表达或功能。使用靶向siRNA敲低和一种新的在基因敲除小鼠中，我们发现polyI：C诱导的上皮细胞因子基因表达和中性粒细胞肺的募集都依赖于PKD 3。这似乎涉及到一个以前没有报道过的 PKD 3在上皮细胞中polyI：C信号传导以及趋化因子受体信号传导中的作用中性粒细胞的转导。令人兴奋的是，我们还发现一种有效的选择性PKD拮抗剂，保护小鼠免受甲型流感病毒（IAV）感染。在此修订的R 01应用程序中，我们建议三个目标：准确解释PKD如何介导气道上皮细胞中的dsRNA信号转导细胞（目标1），使用条件删除和其他策略来解开一个新的中性粒细胞特异性作用， PKD 3在肺部炎症中的作用（目的2），并检验靶向PKD将减弱肺部炎症的假设。小鼠流感感染后的炎症（目的3）。