The goal of my proposecJ research is to characterize lipid-mediated lateral organization in cell plasma membranes and to decipher the underlying physical mechanisms that give rise to this structure. In so doing, I will surmount significant barriers currently facing cell membrane research by developing new experimental tools to manipulate and test the functional consequences of lipid-mediated organization in living cells. My past success in deciphering liquid immiscibility in simple model membranes forms the foundation for my current and future studies in biological membranes. In my early postdoctoral work with Baird Laboratory at Cornell University, I identified robust critical fluctuations in plasma membrane vesicles isolated from RBL mast cells. This result strongly supports my working hypothesis that critical fluctuations are present in cell plasma membranes at physiological temperatures. In the mentored stage of this award, I have implemented experimental and analytic techniques to quantify and interpret nanometer-size organization on the intact cell surface (Aim 1), and I have investigated the functional effects of plasma membrane composition and structure on the IgE-mediated signaling pathway in RBL mast cells (Aim 2). Through these studies, I successfully applied this quantitative and biophysically motivated approach to this biomedically relevant area of research. As an independent researcher, I will continue work on both aims, eventually deciphering the physical basis of membrane lateral organization (Aim 1), and developing novel methodologies to probe the functional consequences of lipid-mediated lateral heterogeneity in antigen induced immune cell signaling processes (Aim 2). My long term goal is develop general methods to probe the functional roles of lipids in a wide range of processes and cell types which will enable new lines of study into the biomedical consequences of lipid mediated plasma membrane organization in cells. The Pathway to Independence Award has given me the independence to focus deeply on my biological training in my postdoctoral years, and the resources to smoothly transition into my current independent faculty position.
It is widely accepted that plasma membrane lateral heterogeneity plays important functional roles in normal cell processes and in the development and maintenance of human diseases. I will open new opportunities for intervention in cell membrane-based pathologies by developing effective experimental techniques and a clear conceptual framework in which to study lipids and proteins in native membranes.
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