Mechanisms of Reovirus Bloodstream Dissemination

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s1 s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阻滞和凋亡中发挥作用。然而，目前还不知道这些过程是否负责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，以确定如何s1s有助于呼肠孤病毒诱导的细胞周期停滞，细胞凋亡和全身传播。第一个具体的目标是确定细胞周期扰动和凋亡诱导所需的s1序列，并确定参与破坏细胞周期进程的细胞因子，以响应呼肠孤病毒感染。第二个具体目标将确定s1s介导的细胞周期阻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，这些研究将有助于广泛的病毒致病机制的研究，通过提高病毒传播的分子和细胞基础的理解，并提供重要的新的见解病毒感染调节宿主细胞周期和疾病的高潮机制。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，希望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。我将开始申请研究赠款，包括一个行政长官发起的R01申请。K22职业发展奖的申请已经提交，以提高实现这两个目标的前景。在我的职业生涯中，我所接受的培训为我从博士后到独立实验室团队领导者的过渡做好了充分的准备。该奖项将提高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赠款申请的基础。

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.