Interferon Effector Gene Activation to Circumvent Viral Impedance

描述(申请人提供)：许多临床相关病毒缺乏或不能获得抗病毒治疗，如黄病毒登革热和西尼罗河病毒。针对宿主的抗病毒药物可以提供一种有效的策略来治疗病毒感染。拟议的研究和总体职业发展计划的目的是为广泛作用的抗病毒设计确定具体的、合理的宿主目标。候选人是一名内科科学家，对基础科学研究有着极其坚定的承诺，他的长期职业目标是成为宿主-病毒相互作用领域的独立研究员，并为改进的抗病毒疗法的发展做出有意义的贡献。具体地说，她希望有助于我们理解推动宿主干扰素介导的抗病毒反应的机制。应聘者的短期职业目标是(1)精通新的遗传、生化和病毒学技术；(2)将这些技术应用于确定干扰素抗病毒作用的机制；(3)发展专业知识，促进病毒学、遗传学、细胞生物学和系统生物学专家之间富有成效的合作；以及(4)提供足够的初步数据和出版物，以供竞争申请 R01资助，作为学术医学研究事业的基础。拟议项目的总体主题是了解干扰素(干扰素)如何抑制黄病毒。宿主分子干扰素是已知的最广泛的作用抗病毒药物之一。为了更好地了解干扰素如何抑制病毒感染，进行了全基因组小干扰RNA筛选，以确定抑制完全感染性丙型肝炎病毒的干扰素效应基因。屏幕识别出PPAR？DNA结合结构域相互作用蛋白1(PDIP1)是一种得分最高的干扰素效应因子。PDIP1的抗病毒作用机制完全未知。这项研究的具体目的是检验两个基本假设：1)一组离散的宿主IEG，如PDIP1，具有广泛的临床相关抗黄病毒活性，其活性位于病毒阻抗下游；2)IEG PDIP1通过耗尽病毒复制所需的宿主脂类来介导广泛的抗病毒作用。TE建议的工作将在一个结构化的职业发展计划的背景下进行，该计划将允许应聘者获得遗传、生物化学和细胞生物学方法方面的专业知识，以研究宿主抗病毒防御。这些研究将得到丙型肝炎病毒学家Raymond Chung博士与遗传学家Stephen Elledge博士和PDIP1专家Tetsurou Satoh博士的高度合作指导，并由系统生物学家Ramnik Xavier博士提供意见，这两人将共同组成候选人的正式研究咨询委员会。研究环境包括MGH GI部门和哈佛医学院教员的动态研究社区，并将提供一个丰富、鼓舞人心和支持的环境，在这种环境中，Fusco博士将能够充分发挥她作为一名独立的、由R01资助的研究员的潜力。

DESCRIPTION (provided by applicant): Antiviral therapies are lacking or inadequate for many clinically relevant viruses, such as the Flaviviridae dengue and West Nile Virus. Host-targeted antivirals can provide an effective strategy to treat viral infections. The aim of the proposed research and overall career development plan is to identify specific, rational host targets for broad-acting antiviral design. The candidate is a physician-scientist with an extremely strong commitment to basic science research whose long term career goal is to become an independent investigator in the field of host-virus interactions and to make meaningful contributions to the development of improved antiviral therapy. Specifically, she hopes to contribute to our understanding of the mechanism driving host interferon-mediated antiviral response. The candidate's short term career goals are (1) to become proficient in new genetic, biochemical, and virological techniques; (2) to apply those techniques toward identifying the mechanism of interferon antiviral effects; (3) to develop professional expertise in fostering productive collaborations between experts in virology, genetics, cellular biology, and systems biology; and (4) to produce sufficient preliminary data and publications to apply competitively for R01 funding as the basis of a career in academic medical research. The overall theme of the proposed project is to understand how interferon-¿ (IFN¿) inhibits Flaviviridae. The host molecule IFN¿ is one of the broadest acting antivirals known. To better understand how IFN¿ inhibits viral infection, a genome-wide small interfering RNA screen was performed to identify interferon effector genes that inhibit fully infectious HCV. The screen identified PPAR? DNA binding domain interacting protein 1 (PDIP1) as a top scoring IFN effector. The mechanism of PDIP1 antiviral activity is wholly unknown. The specific aims of this study are to test two fundamental hypotheses: 1) a discrete set of host IEGs such as PDIP1 have broad, clinically relevant antiflaviviral activity that is active downstream of viral impedance and 2) the IEG PDIP1 mediates broad antiviral effects through depletion of host lipids required for viral replication. Te proposed work will be pursued within the context of a structured career development program which will allow the candidate to acquire expertise in genetic, biochemistry, and cellular biology approaches to studying host antiviral defense. These studies will be supported by the highly collaborative mentorship of Dr. Raymond Chung, a hepatitis C virologist, in collaboration with Dr. Stephen Elledge, a geneticist, and Dr. Tetsurou Satoh, a PDIP1 expert, with input from Dr. Ramnik Xavier, an expert systems biologist, who will together form a formal research advisory committee for the candidate. The research environment includes the dynamic research community of the MGH GI Division and Harvard Medical School faculty and will provide an enriching, inspiring and supportive climate in which Dr. Fusco will be able to achieve her full potential as an independent, R01-funded investigator.