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Isoform-specific Regulation of the Coxsackie and Adenovirus Receptor in Polarized Epithelia

极化上皮细胞中柯萨奇和腺病毒受体的亚型特异性调节

基本信息

批准号：
8879657
负责人：
Katherine Julie Excoffon
金额：
$ 44.4万
依托单位：
WRIGHT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-22 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8879657
关键词：
Acute Adenovirus Infections Adenoviruses Adhesions Affect Air Alternative Splicing Apical BAIAP1 gene Binding CAR receptor Cells Cellular biology Cessation of life Coxsackie B Viruses Coxsackie Viruses Coxsackievirus Infections Data Degradation Pathway Disease Outbreaks Down-Regulation Endoplasmic Reticulum Environment Epithelial Epithelial Cells Epithelium Exons Family Goals Health Human Infection Inherited Innovative Therapy Knowledge Lead Lipids Location Lung Lung diseases Malignant Neoplasms Mediating Medicine Methodology Microbe Military Personnel Molecular Molecular Virology Pathogenesis Pathway interactions Peptides Predisposition Prevention Productivity Protein Isoforms Proteins Quality Control RNA Splicing Regulation Research Scaffolding Protein Side Sorting - Cell Movement Sterility Structure Surface Techniques Testing Therapeutic Therapeutic Index Therapeutic Intervention Tight Junctions Tonsil Training Universities Vaccination Viral Viral Pathogenesis Viral Pneumonia Viral Vector Virus Virus Diseases Virus Receptors Work adenoviral-mediated adenovirus receptor airway epithelium apical membrane base basolateral membrane clinically significant college gene therapy gene therapy clinical trial glycosylation graduate student human disease improved insight interstitial mathematical sciences member membrane-associated guanylate kinase microbial mimetics novel pathogen prevent protein degradation protein expression public health relevance receptor receptor expression trafficking undergraduate student virology

项目摘要

DESCRIPTION (provided by applicant): Adenovirus is a common human pathogen that was first identified from tonsils in 1953. Over the past 6 decades, adenovirus research has yielded impressive knowledge about the pathogenesis of viral pneumonias, vaccination, and basic aspects of molecular virology and cellular biology. However, adenovirus remains a significant civilian and military threat since no specific therapeutic treatment for adenoviral infection exist. Adenovirus is also clinically significant because it is the most common viral vector used in human gene therapy clinical trials. New techniques that enhance adenovirus infection would, thus, improve the therapeutic index of these innovative therapies. Most adenoviruses and group B coxsackieviruses share a common receptor: coxsackievirus and adenovirus receptor (CAR). A major unanswered question has been how these pathogenic viruses initiate infection from the air-exposed lung epithelial surface. Our group has recently discovered that one of the two transmembrane isoforms of CAR (CAREx8) can localize at the air-exposed apical epithelial surface. Moreover, we have found that a cellular scaffolding protein, membrane-associated guanylate kinase with inverted domain structure 1 (MAGI-1), serves as a master negative regulator for cellular CAREx8 protein expression levels and apical adenovirus entry. Understanding the mechanism by which MAGI-1 regulates CAREx8 may lead to novel and specific therapeutics able to alter the susceptibility of an epithelium to adenovirus infection. We hypothesize that MAGI-1 downregulates CAREx8 protein expression by marking CAREx8 as a substrate for the protein-surveillance endoplasmic reticulum associated-degradation (ERAD) pathway. We further hypothesize that molecules that block the MAGI-1-CAREx8 interaction will directly affect the susceptibility of an epithelium to adenovirus infection. We aim to understand the molecular basis of MAGI- 1-mediated CAREx8 down regulation and whether specific cell-permeable peptides can interrupt this interaction to either decrease or increase apical adenovirus infection in polarized epithelia. Understanding these molecular mechanisms is clinically significant for several reasons. Currently there is no specific treatment for coxsackievirus or adenovirus infection; thus, the ability to block virus binding in the face of virl outbreaks would be a significant therapeutic advance. On the other hand, the ability to augment apical expression of the receptor would have high relevance for efficient adenoviral-mediated gene therapy for lung diseases, such as cancer. Finally, this work will expose a team of graduate and undergraduate students to vital research at the interface of virology and medicine.

描述（由申请方提供）：腺病毒是一种常见的人类病原体，于1953年首次从扁桃体中发现。在过去的60年里，腺病毒研究已经取得了令人印象深刻的知识，病毒性肺炎的发病机制，疫苗接种，以及分子病毒学和细胞生物学的基本方面。然而，腺病毒仍然是一个重大的民用和军事威胁，因为没有具体的治疗治疗腺病毒感染存在。腺病毒也具有临床意义，因为它是人类基因治疗临床试验中最常见的病毒载体。因此，增强腺病毒感染的新技术将提高这些创新疗法的治疗指数。大多数腺病毒和B组柯萨奇病毒共享一个共同的受体：柯萨奇病毒和腺病毒受体（CAR）。一个主要的未回答的问题是这些致病病毒如何从暴露于空气的肺上皮表面开始感染。我们的小组最近发现CAR的两种跨膜亚型之一（CARex 8）可以定位于暴露于空气的顶端上皮表面。此外，我们已经发现，细胞支架蛋白，膜相关的鸟苷酸激酶与反向结构域结构1（MAGI-1），作为一个主负调节细胞CAREx 8蛋白表达水平和顶端腺病毒进入。了解MAGI-1调节CARex 8的机制可能会导致能够改变上皮对腺病毒感染的易感性的新型和特异性治疗方法。我们假设MAGI-1通过将CARex 8标记为蛋白质监视内质网相关降解（ERAD）途径的底物来下调CARex 8蛋白表达。我们进一步假设阻断MAGI-1-CARex 8相互作用的分子将直接影响上皮对腺病毒感染的易感性。我们的目的是了解MAGI- 1介导的CARex 8下调的分子基础，以及特定的细胞渗透性肽是否可以中断这种相互作用，以减少或增加极化上皮中的顶端腺病毒感染。了解这些分子机制具有临床意义，原因有几个。目前还没有针对柯萨奇病毒或腺病毒感染的特异性治疗方法;因此，在病毒爆发时阻断病毒结合的能力将是一个重大的治疗进展。另一方面，增强受体顶端表达的能力与有效的腺病毒介导的肺部疾病如癌症的基因治疗具有高度相关性。最后，这项工作将使一个研究生和本科生团队在病毒学和医学的界面上进行重要的研究。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The PDZ3 domain of the cellular scaffolding protein MAGI-1 interacts with the Coxsackievirus and adenovirus receptor (CAR).

细胞支架蛋白 MAGI-1 的 PDZ3 结构域与柯萨奇病毒和腺病毒受体 (CAR) 相互作用。

DOI：
10.1016/j.biocel.2015.01.012
发表时间：
2015
期刊：
The international journal of biochemistry & cell biology
影响因子：
0
作者：
Yan,Ran;Sharma,Priyanka;Kolawole,AbimbolaO;Martin,SterlingCT;Readler,JamesM;Kotha,PoornimaLN;Hostetler,HeatherA;Excoffon,KatherineJDA
通讯作者：
Excoffon,KatherineJDA

Sidestream smoke exposure increases the susceptibility of airway epithelia to adenoviral infection.

横向烟雾暴露增加了气道上皮对腺病毒感染的敏感性。