The functional organization of mammalian membranes

哺乳动物膜的功能组织

• 批准号: 10727014
• 负责人: Ilya Levental
• 金额: $ 1.83万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10727014
• 关键词: Address; Affinity; Biophysics; Cardiovascular Diseases; Cell membrane; Cell physiology; Cells; Code; Complex; Coupled; Dietary Fatty Acid; Disease; Functional disorder; Goals; Homeostasis; Laboratories; Lateral; Life; Lipids; Malignant Neoplasms; Mammalian Cell; Membrane; Membrane Fluidity; Membrane Protein Traffic; Methodology; Microscopy; Phenotype; Predisposition; Property; Proteins; Research; Resolution; Role; Structure; Therapeutic; Trees; Work; biophysical analysis; computer framework; design; dietary; immune activation; insight; lipidome; lipidomics; novel therapeutic intervention; physical property; public health relevance; response; treatment strategy

PROJECT SUMMARY Our laboratory investigates the functional organization of mammalian membranes to generate mechanistic insight into the connections between lipid composition, membrane structure, and cell physiology. Membranes host a major fraction of all cellular bioactivity, orchestrating myriad simultaneous, parallel tasks. This functionality is enabled by the remarkable complexity and diversity of mammalian lipidomes, which give rise to a unique combination of biophysical phenotypes, including membrane fluidity, tension, curvature, and lateral compartmentalization. We aim for a predictive understanding of how lipidomic features determine membrane properties, and how these in turn regulate cell functions. Progress towards this goal has been enabled by recent methodological advances in high-throughput lipidomics, biophysical analysis of plasma membranes, and quantitative high-resolution spectral microscopy. Using these, we have made significant advances in understanding several interrelated aspects of lateral and transverse organization of mammalian membranes. We have defined broad structural features responsible for protein association with ordered membrane domains and how such domains are involved in membrane traffic. Despite these insights, there remains remarkably little known about which proteins associate with membrane domains and why. Our experimental and computational framework allows us to address key outstanding questions, including: what are the structural codes for protein affinity for ordered domains, and how does protein association with membrane domains facilitate their localization and function? In parallel, we have characterized the remarkable plasticity of mammalian membranes (particularly their susceptibility to dietary fatty acids) and characterized the effects of external inputs on membrane properties and cell function. However, how cells maintain membrane homeostasis in response to continuous challenge from dietary and other external inputs is not well understood. Our observations suggest that interference with such homeostatic mechanisms may provide a novel therapeutic strategy for treatment of cardiovascular disease or cancer. Finally, our most recent work has focused on the asymmetric distribution of lipids between the two leaflets of the plasma membrane bilayer. Although such compositional asymmetry appears to be a universal design principle for living membranes, the selective advantages that asymmetry confers are not known. We are defining the compositional, biophysical, and functional asymmetry of the plasma membrane in mammalian cells to answer major open questions about the biophysical consequences of membrane asymmetry and how physical properties are coupled across asymmetric leaflets. Functionally, intriguing recent discoveries reveal that transient loss of membrane asymmetry is widespread during immune activation, and is necessary for optimal response; however, the mechanisms underlying these effects of transient lipid scrambling are unknown. Addressing these questions will advance our understanding of the functional role of membrane organization across the tree of life.

项目摘要 我们的实验室研究了哺乳动物膜的功能组织，以产生机械的 深入了解脂质组成，膜结构和细胞生理学之间的联系。膜 拥有所有细胞生物活性的主要部分，协调无数同时并行的任务。这 哺乳动物脂质体的显著复杂性和多样性使其功能成为可能， 生物物理表型的独特组合，包括膜流动性、张力、曲率和横向 划分我们的目标是预测了解脂质组学特征如何决定膜 性质，以及它们如何反过来调节细胞功能。在实现这一目标方面取得了进展， 高通量脂质组学，质膜的生物物理分析， 和定量高分辨率光谱显微镜。利用这些，我们在以下方面取得了重大进展： 了解哺乳动物膜的横向和横向组织的几个相互关联的方面。 我们已经定义了负责蛋白质与有序膜结构域结合的广泛结构特征 以及这些结构域如何参与膜运输。尽管有这些见解， 了解哪些蛋白质与膜结构域相关以及为什么相关。我们的实验和计算 框架使我们能够解决关键的悬而未决的问题，包括：什么是蛋白质的结构代码 有序结构域的亲和力，以及蛋白质与膜结构域的结合如何促进它们的 定位与功能？与此同时，我们已经描述了哺乳动物的显著可塑性， 膜（特别是它们对膳食脂肪酸的敏感性），并表征了外部 细胞膜特性和细胞功能的输入。然而，细胞如何维持膜稳态， 对来自饮食和其他外部输入的持续挑战的反应尚不清楚。我们 观察表明，干扰这种稳态机制可能会提供一种新的治疗方法， 用于治疗心血管疾病或癌症策略。最后，我们最近的工作集中在 脂质在质膜双层的两个小叶之间的不对称分布。虽然这样 组成的不对称性似乎是活膜的通用设计原则， 不对称性带来的优点是未知的。我们正在定义成分，生物物理， 哺乳动物细胞质膜的功能不对称性，以回答有关 膜不对称性的生物物理后果以及物理特性如何耦合 不对称的小叶。在功能上，最近有趣的发现表明， 不对称性在免疫激活期间广泛存在，并且是最佳应答所必需的;然而， 这些瞬时脂质扰乱效应的潜在机制是未知的。解决这些问题 将促进我们对膜组织在生命之树中的功能作用的理解。