Cellular Receptors for the Human Polyomaviruses

人类多瘤病毒的细胞受体

基本信息

批准号：
7483699
负责人：
Walter J Atwood
金额：
$ 25.73万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7483699
关键词：
Amino Acids BK Virus Binding Biology Capsid Proteins Cell Communication Cell Nucleus Cell membrane Cells Complex Coupled Data Demyelinating Diseases Disease Dominant-Negative Mutation Functional disorder Funding G-Protein-Coupled Receptors Glycoproteins Goals Growth Human Imaging technology Immunocompromised Host Individual Infection Invaded JC Virus Kidney Kidney Diseases Kidney Transplantation Lead Life Cycle Stages Link Malignant Neoplasms Maps Minor Molecular Molecular Genetics Morbidity - disease rate Mutagenesis NMR Spectroscopy Neuraxis Pathogenesis Pathway interactions Polyomavirus Progressive Multifocal Leukoencephalopathy Proteins Receptor Cell Role Role playing therapy Sialic Acids Signal Pathway Signal Transduction Site Site-Directed Mutagenesis Sorting - Cell Movement Specificity Testing Tissues Transplant Recipients Tropism Viral Viral Proteins Virus Virus Diseases Virus Receptors Work base immunosuppressed inhibitor/antagonist insight mortality mutant novel prevent receptor receptor binding recombinant virus research study response serotonin receptor trafficking

项目摘要

DESCRIPTION (provided by applicant): The human polyomaviruses, JCV and BKV, establish lifelong persistent infection in kidney but are generally not associated with disease in healthy individuals. In immunosuppressed patients reactivation and spread of JCV to the central nervous system causes a fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML). Reactivation of BKV in immunosuppressed renal transplant patients causes polyomavirus associated nephropathy (PVN) that leads to graft dysfunction and loss. Viral DMA and viral gene products from both JCV and BKV have been detected in human cancers but a causal link has not been established. Our long-term goals are to define the role of virus receptors in cellular invasion, spread, and pathogenesis. During the last funding cycle we discovered that the JCV receptor is a complex consisting of alpha(2,6) linked sialic acid and the 5HT2a receptor. Both components are critical for infection as cells missing either component are not susceptible to infection by JCV. Our efforts are now focused on identifying the critical determinants that allow JCV to productively interact with this receptor complex. As the 5HT2a receptor is a G protein coupled receptor and JCV binding to cells induces a signal that is essential for infection we will determine whether JCV signals directly through this receptor. During the last funding cycle we discovered that the receptor for BKV is an N-linked glycoprotein containing alpha(2,3)-linked sialic acid, that signaling is important for BKV infection, and that BKV does not share receptor specificity with JCV. A detailed molecular genetics approach is proposed to identify the critical residues in the BKV capsid protein VP1 that interacts with sialic acid containing receptors. We will also compare JCV and BKV induced signaling and entry pathways in the cell. Our specific aims are to 1. define the interactions between human polyomavirus capsid proteins and host cell receptors, 2. define the molecular pathways that link virus- induced signaling at the plasma membrane to transcriptional responses in the nucleus, and 3. map the infectious entry pathway leading to the nucleus and identify the viral and cellular proteins involved at each step. Data resulting from these studies will yield novel insights into the pathogenesis of human polyomavirus induced disease and may lead to novel therapies to prevent or treat these diseases.

描述（由申请人提供）：人类多瘤病毒，JCV和BKV，在肾脏中建立终身持续感染，但通常与健康个体中的疾病无关。在免疫抑制的患者重新激活和JCV对中枢神经系统的扩散会导致致命的脱髓鞘疾病，称为进行性多灶性白细胞术（PML）。 BKV在免疫抑制的肾移植患者中的重新激活会导致多瘤病毒相关的肾病（PVN），导致移植功能障碍和损失。在人类癌症中已经检测到来自JCV和BKV的病毒DMA和病毒基因产物，但尚未建立因果关系。我们的长期目标是定义病毒受体在细胞侵袭，扩散和发病机理中的作用。在上一个融资周期中，我们发现JCV受体是由α（2,6）连接的唾液酸和5HT2A受体组成的复合物。两种成分对于感染至关重要，因为缺少任何成分的细胞都不容易受到JCV感染的影响。现在，我们的努力专注于确定允许JCV与该受体复合物有效相互作用的关键决定因素。由于5HT2A受体是G蛋白偶联受体，JCV与细胞的结合诱导了一种对感染至关重要的信号，因此我们将确定JCV信号是否直接通过该受体信号。在上一个融资周期中，我们发现BKV的受体是含有α的N连接糖蛋白（2,3）链接的唾液酸，该信号对于BKV感染很重要，并且BKV不与JCV共享受体特异性。提出了一种详细的分子遗传学方法，以鉴定与含有唾液酸含有受体的BKV衣壳蛋白VP1中的临界残基。我们还将比较JCV和BKV诱导的信号传导和细胞中的进入途径。我们的具体目的是1。定义人类多瘤病毒capsID蛋白与宿主细胞受体之间的相互作用，2。定义分子途径，这些分子途径将质膜的病毒诱导的信号连接到核中的转录反应，并绘制3。映射感染性入口途径，导致了核和细胞蛋白涉及各个病毒素和细胞蛋白。这些研究产生的数据将产生对人多瘤病毒诱导疾病发病机理的新见解，并可能导致预防或治疗这些疾病的新疗法。