Exploring serine arginine rich splicing factors and serine arginine protein kinase on rhinovirus infection in airway epithelial cell function

学生奖学金战略优先领域：基础生物科学支撑健康关键词：鼻病毒C，剪接因子，儿科慢性哮喘如何改变呼吸道上皮基因表达以优化小核糖核酸病毒的病毒生产，鼻病毒C仍然不确定。研究表明，病毒可以通过转录后RNA加工和输出、mRNA稳定性和核糖体上的mRNA翻译的失调来做到这一点。我们最近完成了对鼻上皮细胞的转录组学分析，这些细胞是从鼻病毒A和C感染的哮喘前期儿童中获得的。鼻病毒A和鼻病毒C具有不同的细胞进入机制，并且毫不奇怪，我们已经发现了已知宿主蛋白质的基因表达模式的几个差异，这些差异可以解释对这些病毒的反应严重性的差异。除了已知的参与免疫反应和宿主防御的途径外，我们还发现了这些病毒如何篡夺上皮细胞机制的潜在分子机制。换句话说：丝氨酸/精氨酸蛋白激酶1（SRPK 1）-通过调节剪接因子的细胞内定位的组成性和选择性宿主RNA剪接的调节剂，和富含丝氨酸/丝氨酸的剪接因子（例如SRSF 6）-这些蛋白质及其被特定蛋白激酶（特别是SRPK 1）磷酸化，构成调控组成性和选择性前mRNA剪接的控制回路，并在细胞中协调剪接与转录。令人惊讶的是，我们已经观察到SRPK 1和一些SRSF 2、SRSF 6、SRSF 9和SRSF 11的表达水平之间存在良好的相关性。同样有趣的是，SRPK 1已被报道磷酸化一些SRSF，包括SRSF 2和SRSF 6。尽管SRPK 1直接调节SRSF蛋白磷酸化的选择性剪接，但对SRSF 6的功能知之甚少。最后，SRPK 1抑制剂具有抗丙型肝炎病毒、HIV和辛德毕斯病毒以及巨细胞病毒的抗病毒活性。鼻病毒感染人鼻上皮细胞引起的这些体内转录组学变化对SRSFs磷酸化/活性（宿主细胞RNA剪接）及其对上皮细胞功能和宿主防御以及鼻病毒复制的影响的意义尚不清楚。以确定SRPK 1-SRSF 6轴是否控制特定的宿主剪接事件。了解SRPK 1-SRSF 6轴的调节是否对上气道上皮功能有重要作用.了解SRPK 1-SRSF 6轴的调节是否对鼻病毒如何控制上皮基因表达以优化病毒生产很重要。

Studentship strategic priority area:Basic Bioscience Underpinning HeathKeywords:Rhinovirus C, splicing factors, paediatric chronic asthma How respiratory epithelial gene expression is altered in order to optimize viral production for the picornavirus, rhinovirus C is still uncertain. Studies have suggested that viruses can do this by the dysregulation of post-transcriptional RNA processing and export, mRNA stability and mRNA translation on the ribosome. We have recently completed a transcriptomics analysis of nasal epithelial cells obtained from children with pre-asthma infected with rhinovirus A and C. Rhinovirus A and C have different cellular entry mechanisms and unsurprisingly we have found several differences in the gene expression pattern of know host proteins that could explain the differences in the severity of response to these viruses. In addition to the known pathways involved in immune response and host defence we have uncovered potential molecular mechanisms for how these viruses may usurp the epithelial cell's machinery. Namely by altering:. serine/arginine protein kinase 1 (SRPK1) - a regulator of both constitutive and alternative host RNA splicing by regulating intracellular localization of splicing factors and. serine/arginine-rich splicing factors (e.g. SRSF6) - these proteins and their phosphorylation by specific protein kinases, particularly SRPK1, constitute control circuits to regulate both constitutive and alternative pre-mRNA splicing and coordinate splicing with transcription in cells. These proteins can also control mRNA export, stability andtranslation.Surprisingly we have observed a good correlation between expression levels of SRPK1 and some SRSFs including SRSF2, SRSF6, SRSF9 and SRSF11. It is also intriguing that SRPK1 has been reported to phosphorylate some SRSFs including SRSF2 and SRSF6. Although, SRSF protein phosphorylation by SRPK1 directly regulates alternative splicing little is known about the function of SRSF6. Finally SRPK1 inhibitors have antiviral activities against Hepatitis C virus, HIV and Sindbis virus and cytomegalovirus. The significance of these in vivo transcriptomic changes caused by rhinoviral infection of human nasal epithelial cells on SRSFs phosphorylation/activity (host cell RNA splicing) and its consequent on epithelial cell function and host defence and rhino-viral replication is not known.This project aims:1. To determine whether the SRPK1 - SRSF6 axis controls specific host splicing events.2. To understand whether the regulation of the SRPK1 - SRSF6 axis is important to upper airway epithelial function.3. To understand whether the regulation of the SRPK1 - SRSF6 axis is important to how rhinovirus exerts controls over epithelial gene expression to optimise viral production.