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TRIM2, a novel host factor that restricts New World Arenavirus infection

TRIM2，一种限制新世界沙粒病毒感染的新型宿主因子

基本信息

批准号：
8852547
负责人：
SUSAN R ROSS
金额：
$ 20万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8852547
关键词：
Aerosols Affect Anti-Retroviral Agents Antiviral Agents Apoptosis Arenavirus Arenavirus Infections Argentina Biological Assay Biological Process Bioterrorism Boxing C-terminal Categories Cell Culture Techniques Cell Proliferation Cells Data Dendritic Cells Development Disease Family Future Genes Glycoproteins Goals Health Human Human Pathology Immune response Incidence Infection Integration Host Factors Junin virus Knockout Mice Mediating Modeling Mus Pathway interactions Pharmaceutical Preparations Production Protein Family Proteins RNA Interference RNA Viruses Reagent Rodent Role Small Interfering RNA Specificity TRIM Motif Tacaribe Complex Viruses Testing Therapeutic Vaccines Viral Viral Hemorrhagic Fevers Viral Physiology Virion Virus Virus Diseases Work in vivo macrophage member mortality mouse model novel prevent therapeutic target ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): New world rodent-borne hemorrhagic fever arenaviruses (NWA) such as Junin virus have about a 30% mortality rate. Although an effective Junin virus vaccine has decreased disease incidence, sporadic cases of this as well as the other known and novel NWAs for which there are no vaccines or effective therapeutics still occur. Because they are transmitted by aerosols, these Category A arenaviruses are also potential bioterrorism agents. We recently performed a siRNA screen with pseudotyped viruses bearing the Junin glycoprotein to find host genes involved in entry that could serve as therapeutic targets. We identified a number of genes not previously implicated in virus infection, including TRIM2, a member of the tripartite motif (TRIM) family that includes well-known members of the host's intrinsic defense against viral infections. We showed that TRIM2 is an anti-viral entry host factor. In addition to their antiviral activity, TRIM proteins are involved i a wide range of biological functions including cell proliferation, ubiquitinylation, apoptosis and a variety of human pathologies. Here we will investigate the likely novel mechanism by which TRIM2 restricts NWA infection by carrying out the following aims: Aim 1: Characterize which steps of Junin virus infection are affected by TRIM2. Aim 2: Determine how TRIM2 restricts Junin virus infection. Aim 3: Determine if TRIM2 restricts Junin virus infection in vivo. These studies will allow us to define the potentially unique mechanism by which TRIM2 restricts NWA infection and will allow us to develop critical reagents for future in vivo studies of TRIM2 in virs infection and in normal development.

描述（由申请方提供）：新世界啮齿动物传播的出血热沙粒病毒（NWA），如朱宁病毒，具有约30%的死亡率。尽管有效的朱宁病毒疫苗降低了发病率，但仍然发生这种以及其他已知和新的NWA的散发病例，对于这些病例，没有疫苗或有效的治疗方法。由于它们通过气溶胶传播，这些A类沙粒病毒也是潜在的生物恐怖主义制剂。我们最近进行了一个小干扰RNA筛选与假型病毒轴承的朱宁糖蛋白，以寻找参与进入宿主基因，可以作为治疗目标。我们确定了一些以前没有参与病毒感染的基因，包括TRIM 2，TRIM 2是三重基序（TRIM）家族的成员，包括众所周知的宿主对病毒感染的内在防御成员。我们发现TRIM2是一种抗病毒进入宿主因子。除了它们的抗病毒活性之外，TRIM蛋白还涉及广泛的生物学功能，包括细胞增殖、泛素化、细胞凋亡和多种人类病理学。在这里，我们将调查可能的新机制，TRIM2限制NWA感染，通过执行以下目标：目标1：表征朱宁病毒感染的步骤受TRIM2的影响。目的2：确定TRIM 2如何限制朱宁病毒感染。目的3：确定TRIM 2是否限制体内朱宁病毒感染。这些研究将使我们能够确定TRIM2限制NWA感染的潜在独特机制，并将使我们能够为TRIM2在病毒感染和正常发育中的未来体内研究开发关键试剂。