Asymmetric Lipid Membranes: Innovative model systems with enhanced biological relevance

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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.**