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Encapsidation of adenovirus DNA

腺病毒 DNA 的衣壳化

基本信息

批准号：
7847544
负责人：
MICHAEL J. IMPERIALE
金额：
$ 34.76万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-22 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847544
关键词：
ATP phosphohydrolase Address Adenovirus Infections Adenovirus Vector Adenoviruses Apoptosis Binding Biological Models Capsid Cell Nucleus Cells Childhood Chromosomes Clinical Complex Conjunctivitis Core Protein DNA DNA Binding DNA Packaging DNA biosynthesis Development Diarrhea Disease Elements Escherichia coli Eye Funding Gene Expression Gene Transfer Genome Goals Human Human Adenoviruses Immune system Individual Infection Knowledge Laboratories Lead Left Life Cycle Stages Link Measurement Measures Mutation Oncogenic Patients Persons Pharmaceutical Preparations Play Population Process Proteins RNA chemical synthesis Reaction Recombinant Vaccines Resolution Role Structure Translations Transplant Recipients Upper Respiratory Infections Vaccination Viral Viral Genes Viral Proteins Virion Virus Walker-A Motif ds-DNA gastrointestinal interest mortality mutant particle protein function research study therapy development vector viral DNA

项目摘要

Adenoviruses are small, non-enveloped viruses containing a linear double stranded DNA genome that were first discovered in 1953. The human adenoviruses are associated with a variety of diseases including upper respiratory infections, gastrointestinal illness, and conjunctivitis. Adenovirus infections are a significant clinical problem in transplant recipients, particularly pediatric patients. For many years, these viruses have also been outstanding model systems for the study of DNA replication, RNA synthesis, protein translation, oncogenic transformation, and apoptosis, and more recently interest in adenovirus has expanded due to its potential as a vector for vaccination and human gene transfer studies. Viral gene expression, genome replication, and viral assembly all take place in the nucleus of the infected cell. This project addresses assembly with a focus on the encapsidation of viral DNA. This process requires at least four viral elements: the packaging sequence, which is located near the left end of the genome and is made up of repeated elements called A repeats; the IVa2 protein, which binds to required sequence motifs in this region and is also required for capsid assembly; the L4 22 kDa protein, which forms a complex with the IVa2 protein on the DNA; and the 52/55 kDa protein, which binds both the DNA and the IVa2 protein. The goals of this proposal are to elucidate further the mechanism by which adenovirus encapsidates its DNA, and how this process is linked to capsid formation by the IVa2 protein. The mechanism by which the IVa2 protein facilitates capsid assembly and DNA packaging will be studied by examining the structure of complexes containing the IVa2 and L4 22 kDa proteins and by dissecting the various functions of the IVa2 protein. The role of the 52/55 kDa protein will also be uncovered through the analysis of mutant viruses. These studies will advance our basic understanding of how adenovirus packages its DNA and produces infectious virions. This knowledge will be applicable to the development of anti-viral drugs that block this process, as well as to the development of safer adenovirus vectors and recombinant vaccines.

腺病毒是一种小型无包膜病毒，含有线性双链 DNA 基因组，于 1953 年首次发现。人类腺病毒与多种疾病相关，包括上呼吸道感染、胃肠道疾病和结膜炎。腺病毒感染是移植受者尤其是儿科患者的一个重要临床问题。多年来，这些病毒也被用于研究 DNA 复制、RNA 合成、蛋白质翻译、致癌转化和细胞凋亡的杰出模型系统，并且最近对腺病毒的兴趣由于其作为疫苗接种和人类基因转移研究载体的潜力而扩大。病毒基因表达、基因组复制和病毒组装全部发生在受感染细胞的细胞核中。该项目致力于组装，重点关注病毒 DNA 的衣壳化。这个过程至少需要四个病毒元件：包装序列，位于基因组左端附近，由称为 A 重复序列的重复元件组成； IVa2 蛋白，它与该区域所需的序列基序结合，也是衣壳组装所必需的； L4 22 kDa 蛋白，与 DNA 上的 IVa2 蛋白形成复合物； 52/55 kDa 蛋白，它结合 DNA 和 IVa2 蛋白。该提案的目标是进一步阐明腺病毒包裹其 DNA 的机制，以及该过程如何与衣壳形成联系起来 IVa2 蛋白。通过检查含有 IVa2 和 L4 22 kDa 蛋白的复合物的结构以及剖析 IVa2 蛋白的各种功能，将研究 IVa2 蛋白促进衣壳组装和 DNA 包装的机制。 52/55 kDa 蛋白的作用也将通过突变病毒的分析来揭示。这些研究将增进我们对腺病毒如何包装其 DNA 并产生感染性病毒粒子。这些知识将适用于开发阻断这一过程的抗病毒药物，以及开发更安全的腺病毒载体和重组疫苗。