Functional consequences of plasmalogens - Membrane curvature and lipid miscibility

缩醛磷脂的功能后果 - 膜曲率和脂质混溶性

• 批准号: 10452272
• 负责人: Alison Leonard
• 金额: $ 0.25万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2021-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452272
• 关键词: Address; Affect; Alzheimer' s Disease; Anabolism; Asthma; Binding; Biological; Biological Assay; Biological Models; Biophysics; Brain; Caveolins; Cell membrane; Cells; Cellular biology; Chemicals; Cholesterol; Complex; Coupling; Data; Development; Endocytosis; Esters; Eye; Fellowship; Fluorescence Microscopy; Fluorescence Resonance Energy Transfer; Glycerol; Goals; Health; Heart; Higher Order Chromatin Structure; Homeostasis; Human; Image; Impairment; Individual; Investigation; Kidney; Kinetics; Knowledge; Letters; Link; Lipids; Liquid substance; Liver; Lung; Membrane; Membrane Fluidity; Membrane Fusion; Modeling; National Institute of Child Health and Human Development; Nerve Tissue; Pathway interactions; Phase; Phosphatidylethanolamine; Phospholipids; Physiological; Plasmalogens; Prevalence; Property; Research; Role; Series; Signal Transduction; Structure; Tail; Temperature; Testing; Theoretical model; Training; Transmembrane Transport; Unsaturated Fats; Vertebral column; Vesicle; Work; base; biophysical properties; direct application; ethanolamine plasmalogens; experimental study; graduate student; lipid transport; lipidomics; melting; models and simulation; molecular dynamics; peroxisome; preference; pressure; saturated fat; simulation; skills; trafficking; vinyl ether

Abstract. Functional consequences of plasmalogens—Membrane curvature and lipid miscibility Phosphatidylethanolamine plasmalogen (PEp) is prevalent in mammalian membranes, comprising 20 mol% of phospholipids in the inner leaflet of the plasma membrane (PM) according to recent lipidomics. Despite its prevalence, surprisingly little is known about its biophysical effects on biological membranes. The chemically unique vinyl ether linkage between the glycerol backbone and sn-1 fatty acyl chain is known to increase membrane fluidity and curvature; yet, PEp partitions into more structured cholesterol rich regions of the plasma membrane. Its unique curvature properties and roles in endocytic pathways and cellular signaling suggest it disrupts membrane integrity to promote fusion and fission. The proposed research combines all-atom molecular dynamics (MD) with FRET imaging and membrane fusion assays to quantify the curvature properties of pure PEp and characterize biologically relevant PEp mixtures. The proposal is for an F32 individual training fellowship. As a graduate student, trainee Dr. Alison Leonard (AL) developed an all-atom force field for PEp which she will use in the MD simulations. Whereas AL's graduate research focused on the development of lipid force field parameters and modeling of single-component membranes, the central hypothesis of this proposal addresses a topic with direct application to human health, the mechanisms of lipid homeostasis. AL will expand her knowledge of cell biology and theoretical modeling of biologically relevant lipid mixtures.

抽象的。 血浆肽的功能后果--膜弯曲和脂质 混溶性 磷脂酰乙醇胺缩醛磷脂（PEp）在哺乳动物细胞膜中普遍存在， 在质膜（PM）的内小叶中包含20摩尔%的磷脂， 根据最近的脂质组学。尽管它很流行，但令人惊讶的是， 其对生物膜的生物物理效应。化学性质独特的乙烯基醚 已知甘油主链和SN-1脂肪酰基链之间的连接增加 膜流动性和曲率;然而，PEp分配到更结构化的胆固醇 丰富的区域的质膜。其独特的曲率性质和作用， 内吞途径和细胞信号传导表明它破坏膜的完整性， 促进聚变和裂变。这项研究将全原子分子 动力学（MD）与FRET成像和膜融合测定，以定量 纯PEp的曲率性质和表征生物相关的PEp混合物。 这项建议是关于F32个人训练研究金。作为一名研究生， 博士Alison伦纳德（AL）为PEp开发了一个全原子力场，她将在 MD模拟。而AL的研究生研究集中在发展 脂质力场参数和建模的单组分膜，中央 该建议的假设涉及直接应用于人类健康的主题， 脂质体内平衡的机制。AL将扩大她的细胞生物学知识， 生物相关脂质混合物的理论建模。