Understanding fusion peptide mutations in influenza hemagglutinin

了解流感血凝素的融合肽突变

• 批准号: 8449185
• 负责人: Peter M Kasson
• 金额: $ 28.71万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449185
• 关键词: Affect; Antiviral Agents; Antiviral Therapy; Biological Assay; Biological Models; Capsid Proteins; Cell membrane; Cells; Cessation of life; Chimeric Proteins; Coupled; Data; Defect; Development; Elements; Environment; Experimental Models; Goals; Hemagglutinin; Human; Infection; Influenza; Influenza Hemagglutinin; Knowledge; Laboratories; Length; Life; Lipids; Membrane; Membrane Fusion; Membrane Lipids; Methods; Modeling; Modification; Mutagenesis; Mutation; Nature; Outcome; Pathway interactions; Peptides; Performance; Pharmaceutical Preparations; Phenotype; Point Mutation; Process; Proteins; Sterols; Structural Models; Structure; Study models; Testing; Therapeutic Agents; United States; Vesicle; Viral; Virion; Virus; Work; base; influenzavirus; membrane assembly; molecular scale; mutant; novel therapeutics; pathogen; simulation; theories; therapy development

DESCRIPTION (provided by applicant): Influenza is both a major human pathogen, causing approximately 50,000 deaths per year in the United States and a well-studied model system for cell entry by enveloped viruses. Influenza enters cells via a process of membrane fusion, but despite extensive study the mechanism by which influenza hemagglutinin catalyzes this process is not well understood. Experimental mutagenesis has yielded much data on the functional requirements of influenza fusion proteins, but we have no robust theory that could have predicted these results. This proposal seeks to develop a robust understanding of fusion peptide mechanisms sufficient to predict such mutations to hemagglutinin. We also wish to establish which elements of influenza entry are common to all membrane fusion, as modifications to the lipid environment can also promote or block fusion, and which may be virus-specific. We are developing high-performance simulation methods to analyze membrane fusion; in this work, we will use these methods to predict how mutations to influenza fusion peptides alter the virus's ability to infect cells and to investigate how lipid composition changes interact with these mutations to control viral infectivity. Computational predictions will be evaluated against experimental assays performed in the laboratory of collaborator Steinhauer.

描述（由申请人提供）：流感既是一种主要的人类病原体，每年在美国造成约 50,000 人死亡，也是经过充分研究的包膜病毒进入细胞的模型系统。流感通过膜融合过程进入细胞，但尽管进行了大量研究，但流感血凝素催化这一过程的机制尚不清楚。实验诱变已经产生了有关流感融合蛋白功能要求的大量数据，但我们没有可靠的理论可以预测这些结果。该提案旨在对融合肽机制有一个深入的了解，足以预测血凝素的此类突变。我们还希望确定流感进入的哪些元件是所有膜融合所共有的，因为脂质环境的修饰也可以促进或阻止融合，并且哪些元件可能是病毒特异性的。我们正在开发高性能模拟方法来分析膜融合；在这项工作中，我们将使用这些方法来预测流感融合肽的突变如何改变病毒感染细胞的能力，并研究脂质成分的变化如何与这些突变相互作用以控制病毒的感染性。计算预测将根据合作者斯坦豪尔实验室进行的实验分析进行评估。