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（由申请人提供）：腺病毒是一种常见的人类病原体，于 1953 年首次从扁桃体中被发现。在过去 6 年来，腺病毒研究已经获得了有关令人印象深刻的病毒性肺炎的发病机制、疫苗接种以及分子病毒学和免疫学基础方面的知识。然而，腺病毒仍然是一个重大的民用和军事威胁，因为腺病毒感染还没有具体的治疗方法，因为它是最常见的病毒载体。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 族柯萨奇病毒具有共同的受体：柯萨奇病毒和腺病毒受体（CAR）。这些致病病毒如何从暴露于空气的肺上皮表面引发感染，我们的小组最近发现 CAR 的两种跨膜亚型之一（CAREx8）可以。此外，我们发现一种细胞支架蛋白，即具有反向域结构 1 (MAGI-1) 的膜相关鸟苷酸激酶，可作为细胞 CAREx8 蛋白表达水平的主要负调节因子。了解 MAGI-1 调节 CAREx8 的机制可能会产生能够改变上皮对腺病毒感染的易感性的新型特异性疗法。我们随后，MAGI-1 通过将 CAREx8 标记为蛋白质监视内质网相关降解 (ERAD) 途径的底物来下调 CAREx8 蛋白表达，我们进一步发现阻断 MAGI-1-CAREx8 相互作用的分子将直接影响 CAREx8 的敏感性。我们的目的是了解 MAGI-1 介导的 CAREx8 下调的分子基础以及是否具有特定的细胞渗透性。由于多种原因，肽可以阻断这种相互作用，从而减少或增加顶端腺病毒感染，因此，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。另一方面，增强受体顶端表达的能力对于腺病毒介导的肺部疾病基因治疗具有高度相关性。最后，这项工作将使研究生和本科生团队接触到病毒学和医学交叉领域的重要研究。

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）

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

侧流烟雾暴露会增加气道上皮对腺病毒感染的易感性。

DOI：
发表时间：
2012
期刊：
影响因子：
3.7
作者：
Sharma, Priyanka;Kolawole, Abimbola O;Core, Susan B;Kajon, Adriana E;Excoffon, Katherine J D A
通讯作者：
Excoffon, Katherine J D A

Adenovirus transduction: More complicated than receptor expression.

腺病毒转导：比受体表达更复杂。

DOI：
发表时间：
2017-02
期刊：
影响因子：
3.7
作者：
Sharma, Priyanka;Martis, Prithy C;Excoffon, Katherine J D A
通讯作者：
Excoffon, Katherine J D A

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：
发表时间：
2015-04
期刊：
影响因子：
0
作者：
Yan, Ran;Sharma, Priyanka;Kolawole, Abimbola O;Martin, Sterling C T;Readler, James M;Kotha, Poornima L N;Hostetler, Heather A;Excoffon, Katherine J D A
通讯作者：
Excoffon, Katherine J D A

Accessibility of the coxsackievirus and adenovirus receptor and its importance in adenovirus gene transduction efficiency.

柯萨奇病毒和腺病毒受体的可及性及其在腺病毒基因转导效率中的重要性。