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（由适用提供）：腺病毒是一种常见的人类病原体，于1953年首次从扁桃体中鉴定出来。在过去的60年中，腺病毒研究对病毒性肺炎，疫苗接种，分子病毒学和细胞生物学的基本方面的发病机理产生了令人印象深刻的知识。但是，由于没有针对腺病毒感染的特定治疗治疗，腺病毒仍然是一个重大的平民和军事威胁。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改善这些创新疗法的治疗指数。大多数腺病毒和B组Coxsackievivirus共享一个常见的受体：Coxsackievievivirus和腺病毒受体（CAR）。一个主要的未解决的问题是这些致病性病毒如何从暴露于空气的肺上皮表面感染。我们的小组最近发现，CAR的两个跨膜同工型之一（CAREX8）可以定位在暴露于空气的上皮表面。此外，我们发现，具有倒域结构1（MAGI-1）的细胞支架蛋白质，膜相关的鸟苷酸酯激酶是细胞Carex8蛋白表达水平和顶端腺病毒的主要负调节剂。了解MAGI-1调节Carex8的机制可能导致新颖和特定的疗法可以改变上皮对腺病毒感染的敏感性。我们假设MAGI-1通过将Carex8标记为蛋白质散发性内质网的底物来下调CAREX8蛋白的表达，相关降解（ERAD）途径。我们进一步假设阻断MAGI-1-Carex8相互作用的分子将直接影响上皮对腺病毒感染的敏感性。我们旨在了解大元介导的Carex8下调的分子基础，以及特定的细胞可渗透宠物是否可以中断这种相互作用，以减少或增加偏光性上皮中的根尖腺病毒感染。由于多种原因，了解这些分子机制在临床上具有重要意义。目前尚无针对Coxsackievievivivirus或腺病毒感染的特定治疗方法。因此，面对病毒爆发时阻断病毒结合的能力将是一个显着的热促进。另一方面，增强接收器顶端表达的能力对于有效的腺病毒介导的肺部疾病（例如癌症）具有很高的相关性。最后，这项工作将使一组毕业生和本科生在病毒和医学的界面上进行重要研究。

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.