Macaque Model and Gene Expression Profiling of SARS

SARS 的猕猴模型和基因表达谱

基本信息

批准号：
7568806
负责人：
MICHAEL G KATZE
金额：
$ 62.9万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7568806
关键词：
Adult Respiratory Distress Syndrome Affect Age Alveolar Animal Model Animals Antiviral Response Area Arts Attention Biological Cell Culture System Cell Line Cells Cessation of life Clinical Data Coagulation Process Coronavirus Coronavirus Infections Cultured Cells Data Development Diffuse Disease Disease Outbreaks Disease susceptibility Engineering Epithelial Cells Future Gene Expression Gene Expression Profiling Genes Genomics Goals Growth Hamman-Rich syndrome Human Immune response In Vitro Infection Information Technology Integration Host Factors Interferons Knowledge Lead Learning Lesion Lung Lung diseases Macaca Macaca fascicularis Modeling Molecular Molecular Cloning Morbidity - disease rate Mutation Oligonucleotide Microarrays Pathogenesis Pathway interactions Peripheral Blood Mononuclear Cell Primary Cell Cultures Primary Lesion Pulmonary Pathology Pulmonary alveolar structure Pulmonology RNA Recombinants Research Infrastructure Research Personnel Reserve Cell Respiratory System Respiratory tract structure Role SARS coronavirus Severe Acute Respiratory Syndrome Severities Staging Supporting Cell Symptoms System Technology Therapeutic Time Tissues Universities Vaccines Viral Virulence Virus Virus Diseases Washington base body system experience functional genomics mortality novel diagnostics pathogen pneumocyte programs research study response surfactant virus host interaction

项目摘要

In the winter of 2002-2003 a new viral pathogen, severe acute respiratory syndrome coronavirus (SARS-CoV), rapidly spread across 5 continents, infected over 8,000 people, and caused 774 deaths. The re-emergence of this virus is likely, and much remains to be learned about the molecular basis for its pathogenesis. The most significant organ system affected in fatal SARS cases is the respiratory tract, and of existing animal models, the cynomolgus macaque (Macaca fascicularis) best replicates the pulmonary pathogenesis associated with human SARS. The macaque model was used to prove that SARS-CoV is the primary etiologic agent of SARS, and that type-1 and -2 pneumocytes may be important target cells for SARS-CoV. In this application, our goal is to use the macaque model, primary cell culture systems, infectious molecular SARS-CoV clones, and advanced genomic technologies, to increase our knowledge of SARS-CoV pulmonary pathogenesis. In Specific Aim 1 we will use the macaque model to evaluate the pathogenesis of SARS-CoV and the development of lung disease. We intend to refine the identification of target cells permissive for SARS-CoV and track possible changes in their distribution at different times after infection. The role of age,an important host factor in the severity SARS, will be examined by comparing the development of SARS in macaques of different ages. Macaques will be infected with molecularly cloned wild-type SARS-CoV and SARS-CoV containing mutations in specific accessory genes that may contribute to virulence. Specific Aim 2 will focus on the establishment of an appropriate cell culture system in which to evaluate the cellular response to wild-type and engineered SARS-CoV. This will include studies with < ¿¿ i primary human bronchial and small airway epithelial cells. We also will attempt to infect -macaque primary . type-2 pneumocytes. Finally, Specific Aim 3 will determine molecular meehanisms<and.pathogehic;<:,, So ti signatures of SARS using global gene expression profiling. We will use humaitand;macaque using ck-oai .-; oligonucleotide microarrays and sophisticated information technologies to examin&igene;expression; -UKJ :o; changes in response to SARS-CoV infection. Experiments will be performed using RNA-isolated from in vitro infections and from cells and tissues from experimentally infected macaques. Collectively, data obtained from these studies will provide a better understanding of how SARS-CoV causes lung disease. Such knowledge may lead to new diagnostic, therapeutic, or vaccine strategies, which may serve as important countermeasures to future SARS outbreaks.

2002-2003年冬季，一种新的病毒病原体，严重急性呼吸综合征冠状病毒（SARS-CoV）迅速传播到五大洲，感染了 8,000 多人，并造成 774 人死亡。这种病毒有可能再次出现，其分子基础仍有待了解。致命 SARS 病例中受影响的最重要的器官系统是呼吸道，并且在现有的动物模型中，食蟹猴（Macaca fascicularis）最好地复制了肺与人类 SARS 相关的发病机制使用猕猴模型来证明 SARS-CoV 是病毒。 SARS的主要病原体，1型和-2型肺细胞可能是SARS的重要靶细胞在此应用中，我们的目标是使用猕猴模型、原代细胞培养系统、传染性分子 SARS-CoV 克隆和先进的基因组技术，以增加我们的知识在具体目标 1 中，我们将使用猕猴模型来评估 SARS-CoV 肺部发病机制。我们打算完善 SARS-CoV 的发病机制和肺部疾病的发展。靶细胞允许 SARS-CoV 传播，并追踪其在不同时间分布的可能变化年龄是导致 SARS 严重程度的一个重要宿主因素，我们将通过比较来检验年龄的作用。不同年龄的猕猴都会感染SARS的分子克隆。野生型 SARS-CoV 和 SARS-CoV 含有特定辅助基因的突变，可能有助于具体目标 2 将侧重于建立适当的细胞培养系统。评估细胞对野生型和工程化 SARS-CoV 的反应，这将包括针对 < ¿ ¿我我们还将尝试感染原代人类支气管和小气道上皮细胞。最后，具体目标 3 将确定分子机制<and.pathogehic;<:,, 所以 ti 使用全局基因表达谱分析 SARS 的特征，我们将使用 humaitand;macaque 使用 ck-oai .-; 寡核苷酸微阵列和先进的信息技术来检查&igene;表达；应对 SARS-CoV 感染的变化将使用从 in 中分离的 RNA 进行实验。体外感染以及来自实验感染猕猴的细胞和组织的数据。从这些研究中获得的结果将有助于更好地了解 SARS-CoV 如何引起肺部疾病。这些知识可能会带来新的诊断、治疗或疫苗策略，这些策略可以作为未来SARS爆发的重要对策。

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）

Functional genomics highlights differential induction of antiviral pathways in the lungs of SARS-CoV-infected macaques.

DOI：
10.1371/journal.ppat.0030112
发表时间：
2007-08-10
期刊：
PLoS pathogens
影响因子：
6.7
作者：
de Lang A;Baas T;Teal T;Leijten LM;Rain B;Osterhaus AD;Haagmans BL;Katze MG
通讯作者：
Katze MG

Exacerbated innate host response to SARS-CoV in aged non-human primates.

DOI：
10.1371/journal.ppat.1000756
发表时间：
2010-02-05
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Smits SL;de Lang A;van den Brand JM;Leijten LM;van IJcken WF;Eijkemans MJ;van Amerongen G;Kuiken T;Andeweg AC;Osterhaus AD;Haagmans BL
通讯作者：
Haagmans BL

The application of genomics to emerging zoonotic viral diseases.