Asymmetric Lipid Membranes: Innovative model systems with enhanced biological relevance

不对称脂质膜：具有增强生物相关性的创新模型系统

• 批准号: RGPIN-2018-04841
• 负责人: Marquardt, Drew
• 金额: $ 2.11万
• 依托单位: University of Windsor
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=658809
• 关键词: Asymmetric; Lipid; Membranes; Innovative; model; Asymmetric; Lipid; Membranes; Innovative; model

Cellular membrane functions rely on a diverse scaffold of lipids, sterols, proteins, and carbohydrates. Lipids constitute the largest structural components of biological membranes, and more recently, lipids have been implicated in several disorders including cancer, type II diabetes, and Parkinson, to name a few. Understanding the membrane -- its structure, dynamic behavior and function -- all pose great challenges.******With few exceptions, biological membranes exhibit transmembrane compositional asymmetry with respect to lipid architecture. Most existing research has relied on symmetric model systems, where the inner and outer bilayer leaflets have the same composition. Together with other leaders in my field, we have recently overcome the barrier of generating model membranes with transbilayer asymmetry in an effort to construct more relevant model systems to formulate better theories with a deeper and more fundamental description of biological membranes.******The research goals will be achieved through three key short term objectives. Firstly, my students and I will develop a molecular picture of intra-membrane communication, by 1) investigating the membranes structure in 3 dimensions and 2) the associated lipid and membrane dynamics. The mechanism will be fully realized as we increase complexity of the model (i.e. addition of cholesterol). This work will also bring new insight to the interplay of membrane asymmetry and proteins pertaining to protein insertion. Furthermore, this work will 3) examine membrane properties on a longer scale, namely phospholipid flip-flop. A model of the flip-flop mechanism(s) is key to understanding the levels of energy that cells consume to generate and maintain membrane asymmetry. ******The long-term vision for my research program is the development of an asymmetric model membrane platform to formulate better biological membrane mimics than are currently available to physiologists. The new membrane mimetics will serve as a platform to begin answering fundamental questions about cellular membranes. Furthermore, there are important medical/pharmaceutical implications of asymmetric model membranes which will be realized in the long term.**

细胞膜功能依赖于多种脂质，固醇，蛋白质和碳水化合物的支架。脂质构成了生物膜的最大结构成分，最近，脂质与包括癌症，II型糖尿病和帕金森氏症在内的多种疾病有关，仅举几例。理解膜的结构，动态行为和功能 - 都构成了巨大的挑战。******除了少数例外，生物膜相对于脂质结构表现出跨膜组成的不对称性。大多数现有的研究都依赖于对称模型系统，其中内部和外部双层传单具有相同的组成。与我领域的其他领导者一起，我们最近克服了使用跨贝伊尔不对称产生模型膜的障碍，以构建更相关的模型系统，以对生物膜的更深入，更基本的描述来制定更好的理论。首先，我和我的学生将通过1）研究膜结构在3个维度和2）相关的脂质和膜动力学中开发出膜内通信的分子图。随着我们增加模型的复杂性（即添加胆固醇），该机制将完全实现。这项工作还将为与蛋白质插入有关的膜不对称和蛋白质的相互作用带来新的见解。此外，这项工作将3）较长的比例检查膜特性，即磷脂触发器。触发器机制的模型是了解细胞消耗产生和维持膜不对称性的能量水平的关键。 *****我的研究计划的长期愿景是开发一个不对称模型膜平台，该平台比生理学家目前可用的生物膜模仿更好。新的膜模拟物将作为一个平台，开始回答有关细胞膜的基本问题。此外，从长远来看，不对称模型膜的重要医学/药物含义。**