Project-003

项目-003

基本信息

批准号：
10229090
负责人：
PAUL B MCCRAY
金额：
$ 34.01万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229090
关键词：
Acute Adenovirus Vector Africa Alveolar Amino Acids Animal Model Animals Autopsy Binding Blood Vessels Bone Marrow Brain Camels Cell Communication Cell model Cells Central Nervous System Diseases Chemicals Chimera organism Cleaved cell Codon Nucleotides Coronavirus Coronavirus Infections Country Cytokeratin 18 Dendritic Cells Dipeptides Dipeptidyl Peptidases Dipeptidyl-Peptidase IV Disease Disease Outcome Dromedaries Edema Engineering Epidemic Evolution Exons Fatality rate Genome Growth Factor Health Personnel Hematopoietic Hospitals Human Immune response Infection Infiltration Inflammation Inflammatory Injury Innate Immune Response Interferons K-18 conjugate Knock-in Knock-in Mouse Knockout Mice Knowledge Lead Learning Literature Lung Lung diseases Lung infections Lymphatic Lymphocyte Marrow Mediating Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Modeling Modification Mus Mutate Mutation Operative Surgical Procedures Pathogenesis Pathologic Patients Persons Phenotype Pleural Pneumonia Population Proteins Recombinants Reporting Role SARS coronavirus Serial Passage Serum Specimen Structure of parenchyma of lung Surface Thrombosis Transgenic Organisms Tropism Vaccines Vascular Endothelium Virulence Virulent Virus Virus Replication Zoonoses airway epithelium alveolar epithelium base cell type chemokine comorbidity coronavirus receptor cytokine disease phenotype epidemiology study experimental study gene product genetic information in vivo inhibitor/antagonist insight interest macrophage mortality mouse model novel coronavirus novel therapeutic intervention pathogen promoter protein function receptor transcriptome sequencing vaccine development virology

项目摘要

Project Summary/Abstract Middle East Respiratory Syndrome (MERS) was recognized as a significant illness on the Saudi Arabian peninsula in mid-2012, and the causative agent was rapidly identified as a novel coronavirus (CoV), termed MERS-CoV. MERS has a high mortality (~35%), associated with severe lung disease. Similar to the SARS virus that caused an epidemic in 2003-4, there is ongoing global concern due to MERS high fatality rate. To date, cases of MERS have been reported in 26 countries. Dipeptidyl peptidase 4 (DPP4, CD26) is the receptor for MERS-CoV. Epidemiologic studies have established that MERS is zoonotic in origin, with evidence for a closely related virus in dromedary camels on the Arabian peninsula and throughout Africa. Spread from camels to people is documented, as well as person-to-person spread among health care workers in hospital settings. A lack of autopsy studies from MERS fatalities has hindered understanding of MERS-CoV pathogenesis. Thus, MERS is the most recent confirmation that coronaviruses can jump from their animal hosts, infect humans, and cause severe disease of global significance. There is a pressing need to better understand MERS disease pathogenesis and to develop vaccines and therapies. There are 3 specific aims. Aim 1. To understand how an in vivo evolved MERS-CoV causes lethal lung disease. We developed mice that have the human receptor for MERS-CoV. Using these animals we developed a mouse-adapted virus that causes significant lung disease. These studies will advance our knowledge of the causes of MERS-related lung disease. Aim 2. To investigate how adaptive mutations in MERS-CoV contribute to increased virulence. We sequenced the mouse-adapted virus strains and assembled their genomes. We will use this genetic information to investigate relationships between the virus gene products and the host responses that lead to severe lung disease. Aim 3. To investigate how DPP4 abundance and function influence MERS disease pathogenesis. DPP4 has enzymatic activity that cleaves two amino acids off of target protein substrates, thereby changing protein functions. DPP4 abundance and enzymatic activity may contribute to disease. These experiments will advance our knowledge of how DPP4 activities may underlie to disease outcomes.

项目摘要/摘要中东呼吸道综合征（MERS）被认为是一种重大疾病 2012年中期的沙特阿拉伯半岛，并迅速确定了病原体作为一种新颖的冠状病毒（COV），称为MERS-COV。 MERS具有高死亡率（〜35％），与严重的肺部疾病有关。类似于引起流行病的SARS病毒在2003 - 4年度，由于MERS高死亡率，全球关注的持续关注。迄今为止，在26个国家 /地区报告了MERS病例。二肽基肽酶4（DPP4， CD26）是MERS-COV的受体。流行病学研究已经确定 MERS的起源是人畜共患病，有证据表明在Dromedary Camels中有密切相关的病毒在阿拉伯半岛和整个非洲。从骆驼传播到人是记录在医院的医疗保健工作者中的记录以及人与人之间的传播设置。 MERS死亡的缺乏尸检研究阻碍了人们对 MERS-COV发病机理。因此，MERS是最近确认冠状病毒可以从动物宿主中跳下来，感染人类并引起严重具有全球意义的疾病。迫切需要更好地了解Mers 疾病发病机理并发展疫苗和疗法。有3个具体目标。目的1。了解体内演变的MERS-COV如何导致致命的肺疾病。我们开发了具有MERS-COV的人体受体的小鼠。使用这些动物我们开发了一种小鼠适应的病毒，可引起严重的肺部疾病。这些研究将促进我们对MERS相关肺部疾病的原因的了解。目标2。研究MERS-COV中的自适应突变如何促进毒力增加。我们测序了小鼠适应的病毒菌株并组装他们的基因组。我们将使用这些遗传信息来调查病毒基因产物和导致严重肺部疾病的宿主反应。目的3。研究DPP4丰度和功能如何影响MERS病发病。 DPP4具有酶促活性，可将两个氨基酸从靶标切开蛋白质底物，从而改变蛋白质功能。 DPP4丰度和酶促活动可能导致疾病。这些实验将提高我们对 DPP4活动如何构成疾病结局。