Asymmetric Lipid Membranes: Innovative model systems with enhanced biological relevance

细胞膜的功能依赖于脂类、甾醇、蛋白质和碳水化合物的不同支架。脂类构成生物膜的最大结构成分，最近，脂类与几种疾病有关，包括癌症、II型糖尿病和帕金森等。了解膜--它的结构、动态行为和功能--都是巨大的挑战。除了少数例外，生物膜在脂类结构方面表现出跨膜成分的不对称性。现有的大多数研究都依赖于对称模型系统，其中内外双层小叶具有相同的组成。最近，我们与我所在领域的其他领导者一起，克服了产生跨双层不对称模型膜的障碍，努力构建更相关的模型系统，以制定更好的理论，对生物膜进行更深入、更基本的描述。*研究目标将通过三个关键的短期目标来实现。首先，我和我的学生们将通过1)3维的膜结构和2)相关的脂质和膜动力学来开发膜内通信的分子图像。随着我们增加模型的复杂性(即添加胆固醇)，这一机制将得到充分认识。这项工作还将为膜不对称和与蛋白质插入有关的蛋白质之间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考察膜的性质，即磷脂触发器。触发机制的模型(S)是理解细胞产生和维持膜不对称性所消耗的能量水平的关键。*我研究计划的长期愿景是开发一种不对称模型膜平台，以配制出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，开始回答关于细胞膜的基本问题。此外，不对称模型膜具有重要的医学/药学意义，这将在长期内实现。

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.**