Mechanisms of Reovirus Bloodstream Dissemination

呼肠孤病毒血流传播机制

• 批准号: 8190233
• 负责人: Karl W Boehme
• 金额: $ 16万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-02 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190233
• 关键词: Antibodies; Antigens; Apoptosis; Apoptotic; Applications Grants; Award; B-Lymphocytes; Biological Assay; Blood; Blood Circulation; Cell Cycle; Cell Cycle Arrest; Cell Cycle Progression; Cell Cycle Proteins; Cell Death; Cells; Data; Dendritic Cells; Development; Disease; Faculty; Flow Cytometry; Foundations; Funding; Future; Goals; Hematopoietic; Immunity; Immunologics; Induction of Apoptosis; Intestines; K-Series Research Career Programs; Laboratories; Lead; Link; Lymphatic; M cell; Malignant Neoplasms; Mediating; Mesentery; Molecular; Mus; Nonstructural Protein; Organ; Pathway interactions; Peripheral; Phagocytes; Phosphorylation; Play; Positioning Attribute; Postdoctoral Fellow; Process; Property; Proteins; Proteomics; Reoviridae Infections; Reovirus; Research; Research Personnel; Research Project Grants; Role; Site; Staining method; Stains; Structure of aggregated lymphoid follicle of small intestine; T-Lymphocyte; Testing; Training; Universities; Viral; Viral Pathogenesis; Virus; Virus Diseases; Work; base; career; cell type; college; improved; in vivo; insight; lymph nodes; mutant; neoplastic; protein function; public health relevance; research study; response; trafficking; uptake

DESCRIPTION (provided by applicant): The objective of the proposed research is to determine mechanisms by which mammalian reovirus nonstructural protein s1s promotes systemic viral dissemination. Previous studies and preliminary data indicate that the s1s protein functions in reovirus- induced cell cycle arrest and apoptosis. However, it is not known whether these processes are responsible for s1s-mediated reovirus spread in the infected host. The central hypothesis of these studies is that the s1s protein inhibits host cell cycle progression, leading to apoptotic cell death. Subsequently, apoptotic cells are engulfed by phagocytic cells that transport the virus from the site of inoculation to peripheral organs that support secondary viral replication. Two integrated specific aims are proposed to determine how s1s contributes to reovirus-induced cell cycle arrest, apoptosis, and systemic spread. The first specific aim will define sequences in s1s required for cell cycle perturbation and apoptosis induction, and identify cellular factors involved in disrupting cell cycle progression in response to reovirus infection. The second specific aim will determine the role of s1s-mediated cell cycle arrest and apoptosis in systemic reovirus dissemination in vivo. Collectively, these studies will contribute broadly to viral pathogenesis research by enhancing an understanding of the molecular and cellular bases of viral dissemination, and provide important new insights into mechanisms by which viral infection modulates the host cell cycle and culminates in disease. My near-term career goal is to obtain a position at a college or university where I will lead my own research team. I am currently applying for academic positions and hope to attain a suitable opportunity within the next academic year. I look forward to becoming an independent investigator and building my research team. I will begin by applying for research grants, including an investigator-initiated R01 application. This application for a K22 career development award has been submitted to improve the prospects of achieving both of these goals. The training I have received to this point in my career has prepared me well for the transition from postdoctoral fellow to independent laboratory team leader. This award would enhance the possibility of obtaining a tenure-track faculty position and provide funds to generate preliminary data that will form the foundation of future grant applications. Public Health Relevance: The goal of the experiments described in this proposal is to determine how cell cycle arrest and apoptosis mediated by the reovirus s1s protein contribute to viral pathogenesis. Findings from these studies could lead to new insights into these processes that play fundamental roles in development, immunity, and cancer. Such insights might lead to new treatments for degenerative, immunologic, or neoplastic diseases.

描述（由申请人提供）：拟议研究的目的是确定哺乳动物呼肠孤病毒非结构蛋白 s1s 促进系统性病毒传播的机制。先前的研究和初步数据表明，s1s 蛋白在呼肠孤病毒诱导的细胞周期停滞和细胞凋亡中发挥作用。然而，尚不清楚这些过程是否导致 s1s 介导的呼肠孤病毒在受感染宿主中的传播。这些研究的中心假设是 s1s 蛋白抑制宿主细胞周期进程，导致细胞凋亡。随后，凋亡细胞被吞噬细胞吞噬，吞噬细胞将病毒从接种部位转运到支持二次病毒复制的外周器官。提出了两个综合的具体目标来确定 s1s 如何促进呼肠孤病毒诱导的细胞周期停滞、细胞凋亡和全身传播。第一个具体目标是定义细胞周期扰动和细胞凋亡诱导所需的 s1 序列，并识别响应呼肠孤病毒感染而破坏细胞周期进程的细胞因子。第二个具体目标将确定 s1s 介导的细胞周期停滞和细胞凋亡在体内系统性呼肠孤病毒传播中的作用。总的来说，这些研究将通过增强对病毒传播的分子和细胞基础的理解，为病毒发病机制研究做出广泛贡献，并为病毒感染调节宿主细胞周期并最终导致疾病的机制提供重要的新见解。我的近期职业目标是在学院或大学获得一个职位，在那里我将领导自己的研究团队。我目前正在申请学术职位，并希望在下一学年获得合适的机会。我期待成为一名独立研究者并建立我的研究团队。我将首先申请研究资助，包括研究者发起的 R01 申请。提交 K22 职业发展奖申请是为了改善实现这两个目标的前景。我职业生涯到目前为止所接受的培训为我从博士后研究员到独立实验室团队负责人的转变做好了充分的准备。该奖项将提高获得终身教授职位的可能性，并提供资金来生成初步数据，这些数据将为未来的拨款申请奠定基础。 公共卫生相关性：本提案中描述的实验的目标是确定呼肠孤病毒 s1s 蛋白介导的细胞周期停滞和细胞凋亡如何促进病毒发病机制。这些研究的结果可能会对这些在发育、免疫和癌症中发挥重要作用的过程产生新的见解。这些见解可能会带来退行性、免疫或肿瘤疾病的新疗法。