The functional organization of mammalian membranes

哺乳动物膜的功能组织

• 批准号: 10219653
• 负责人: Ilya Levental
• 金额: $ 14.44万
• 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/10219653
• 关键词: Address; Affinity; Biophysics; Cardiovascular Diseases; Cell membrane; Cell physiology; Cells; Code; Complex; Coupled; Diet; 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; immune activation; insight; novel therapeutics; 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.

项目概要 我们的实验室研究哺乳动物细胞膜的功能组织以产生机制 深入了解脂质成分、膜结构和细胞生理学之间的联系。膜 宿主所有细胞生物活动的主要部分，协调无数同时、并行的任务。这 哺乳动物脂质组的显着复杂性和多样性使功能得以实现，从而产生 生物物理表型的独特组合，包括膜流动性、张力、曲率和横向 区隔化。我们的目标是预测性了解脂质组学特征如何决定膜 特性，以及这些特性如何反过来调节细胞功能。实现这一目标的进展得益于 高通量脂质组学、质膜生物物理分析的最新方法学进展， 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。 我们定义了负责蛋白质与有序膜域关联的广泛结构特征 以及这些域如何参与膜交通。尽管有这些见解，但仍然很少 了解哪些蛋白质与膜结构域相关以及原因。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：蛋白质的结构代码是什么 对有序结构域的亲和力，以及蛋白质与膜结构域的关联如何促进其 定位和功能？与此同时，我们还描述了哺乳动物显着的可塑性 膜（特别是它们对膳食脂肪酸的敏感性）并表征了外部因素的影响 膜特性和细胞功能的输入。然而，细胞如何维持膜稳态 人们对饮食和其他外部输入的持续挑战的反应尚不清楚。我们的 观察表明，干扰这种稳态机制可能提供一种新的治疗方法 治疗心血管疾病或癌症的策略。最后，我们最近的工作重点是 质膜双层的两个小叶之间脂质的不对称分布。虽然这样 成分不对称似乎是活膜的通用设计原则，选择性 不对称带来的优势尚不清楚。我们正在定义成分、生物物理和 哺乳动物细胞质膜的功能不对称性回答了有关 膜不对称的生物物理后果以及物理特性如何耦合 不对称传单。从功能上讲，最近有趣的发现表明，膜的瞬时损失 不对称在免疫激活过程中普遍存在，并且是最佳反应所必需的；然而， 瞬时脂质扰乱这些影响的机制尚不清楚。解决这些问题 将增进我们对生命树中膜组织功能作用的理解。