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Host microRNA control of gammaherpesvirus latency

宿主 microRNA 控制伽马疱疹病毒潜伏期

基本信息

批准号：
9283333
负责人：
Edward J Usherwood
金额：
$ 40.5万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9283333
关键词：
Acquired Immunodeficiency Syndrome Address Affect B cell differentiation B-Lymphocytes Binding Sites Biological Models CD4 Positive T Lymphocytes Cancer Patient Cell Compartmentation Cell Differentiation process Cell physiology Cells Cellular biology Chronic Chronic Disease Complement Data Defect Dependency Disease Environment Exhibits Failure Gene Expression Gene Targeting Genes Growth Helper-Inducer T-Lymphocyte Human Immune Immune response Immunocompromised Host Immunodeficient Mouse Immunologic Surveillance Impairment In Vitro Individual Infection Integration Host Factors Knockout Mice Knowledge Latent Virus Life Lymphoproliferative Disorders Measures Mediating MicroRNAs Modeling Molecular Morbidity - disease rate Mus Organ Transplantation Pathogenesis Patients Plant Roots Plasma Cells Play Population Process Reporter Research Risk Role Source Structure of germinal center of lymph node T-Lymphocyte Testing Therapeutic Transcript Viral Viral Genes Viral load measurement Virus Virus Diseases Virus Latency Virus Replication attenuation cell type cellular targeting combat differentiated B cell disorder risk experimental study gammaherpesvirus immunosuppressed in vivo infected B cell innovation latent infection mortality mouse model novel reactivation from latency response targeted treatment therapeutic target tumor tumor growth

项目摘要

Gammaherpesviruses cause important diseases in immunosuppressed populations, which is due to their ability to establish a latent infection in B lymphocytes. We have learned much about viral gene expression and manipulation of host cell biology during latency. However there is still a notable gap in our knowledge regarding host cell factors required for the efficient establishment of latent infection in vivo. Our research has discovered that mice lacking microRNA-155 (miR-155) have a marked defect in their ability to establish latent infection following murine gammaherpesvirus infection. In this application we will determine the mechanism for this effect, as this will increase our understanding of host cell factors required for efficient latent infection by gammaherpesviruses in an authentic in vivo environment. In our first Specific Aim, we will test whether miR- 155 is acting in a B cell intrinsic fashion, and examine its effect on latent infection and reactivation from latency. We will also determine the molecular mechanisms underlying the effect of miR-155 on latency. The second Specific Aim examines the role of miR-155 in follicular helper CD4 T cell differentiation and function, as this cell type has been shown to be essential for the amplification of latent MHV-68 infection. In the third Specific Aim we will determine whether miR-155 is necessary chronic disease mediated by MHV-68. These experiments will provide important in vivo and mechanistic data to complement current in vitro evidence for a critical role for miR-155 in latent infection with the human gammaherpesviruses. Our data will also reveal whether miR-155 is a potential target that could be manipulated therapeutically to reduce latent virus burden in individuals at risk of severe gammaherpesvirus-related disease.

γ疱疹病毒在免疫抑制人群中引起重要疾病，这是由于它们能够在B淋巴细胞中建立潜伏感染。我们已经了解了很多关于病毒基因表达的知识，在潜伏期期间操纵宿主细胞生物学。然而，我们的知识仍有明显的差距，关于有效建立体内潜伏感染所需的宿主细胞因子。我们的研究发现缺乏microRNA-155（miR-155）的小鼠在建立潜伏性小鼠γ疱疹病毒感染后的感染。在本申请中，我们将确定这种效应，因为这将增加我们对有效潜伏感染所需的宿主细胞因子的理解，在真实的体内环境中的γ疱疹病毒。在我们的第一个具体目标，我们将测试是否miR- 155以B细胞内在的方式起作用，并检查其对潜伏感染和从延迟。我们还将确定miR-155对潜伏期影响的分子机制。的第二个特定目的研究了miR-155在滤泡辅助性CD 4 T细胞分化和功能中的作用，这种细胞类型已被证明对于潜伏的MHV-68感染的扩增是必需的。第三具体目的我们将确定miR-155是否是MHV-68介导的慢性疾病所必需的。这些实验将提供重要的体内和机制数据，以补充目前的体外证据， miR-155在人类γ疱疹病毒潜伏感染中的关键作用。我们的数据还将揭示 miR-155是否是一个潜在的靶点，可以在治疗上进行操作，以减少潜伏病毒的负担，存在严重γ疱疹病毒相关疾病风险的个体。