Asymmetric Lipid Membranes: Innovative model systems with enhanced biological relevance

细胞膜功能依赖于脂质、固醇、蛋白质和碳水化合物的不同支架。脂质构成了生物膜的最大结构组分，并且最近，脂质已经涉及几种疾病，包括癌症、II型糖尿病和帕金森，仅举几例。了解膜的结构、动力学行为和功能都是一个巨大的挑战。除了少数例外，生物膜在脂质结构方面表现出跨膜组成的不对称性。大多数现有的研究依赖于对称模型系统，其中内部和外部双层小叶具有相同的组成。我们与本领域的其他领导者一起，最近克服了生成具有跨双层不对称性的模型膜的障碍，努力构建更相关的模型系统，以更深入和更基本地描述生物膜，从而制定更好的理论。研究目标将通过三个关键的短期目标来实现。首先，我的学生和我将开发一个膜内通信的分子图像，通过1）研究三维的膜结构和2）相关的脂质和膜动力学。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。这项工作也将为膜不对称性和与蛋白质插入有关的蛋白质的相互作用带来新的见解。此外，这项工作将在更长的尺度上研究膜的性质，即磷脂的触发器。翻转机制的模型是理解细胞产生和维持膜不对称性所消耗能量水平的关键。我的研究计划的长期愿景是开发一个不对称模型膜平台，以制定比生理学家目前可用的更好的生物膜模拟物。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，非对称模型膜具有重要的医学/药学意义。

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.