Mechanisms of Reovirus Bloodstream Dissemination

描述(申请人提供)：拟议研究的目标是确定哺乳动物呼肠孤病毒非结构蛋白S1S促进全身病毒传播的机制。以往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，目前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地点运送到支持病毒二次复制的外围器官。提出了两个综合的特定目标，以确定S1S如何促进呼肠孤病毒诱导的细胞周期停滞、凋亡和全身传播。第一个特定目标将定义S1s中细胞周期扰动和诱导细胞凋亡所需的序列，并确定参与扰乱细胞周期进程以响应呼肠孤病毒感染的细胞因子。第二个特定目标将确定S1S介导的细胞周期停滞和凋亡在体内系统性呼肠孤病毒传播中的作用。总之，这些研究将通过加强对病毒传播的分子和细胞基础的了解，为病毒发病机制的研究做出广泛贡献，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。我近期的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，希望能在下一学年获得合适的机会。我期待着成为一名独立的调查员，并建立我的研究团队。我将从申请研究资助开始，包括由研究人员发起的R01申请。提交K22职业发展奖的申请是为了改善实现这两个目标的前景。到目前为止，我所接受的培训为我从博士后到独立实验室组长的转变做好了准备。这一奖项将增加获得终身教职的可能性，并提供资金来生成初步数据，这些数据将成为未来拨款申请的基础。 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凋亡是如何促进病毒致病的。这些研究的发现可能导致对这些过程的新见解，这些过程在发育、免疫和癌症中发挥重要作用。这样的见解可能会为退行性、免疫性或肿瘤性疾病带来新的治疗方法。

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.