Double lipid membrane compartments –cellular containers enveloped by two squishy membranes- are commonly observed in biological cells such as nucleus, chloroplasts and mitochondria. Recently, double membranes were observed in key processes involving autophagy. Autophagy (‘self-eating’) is biology’s way of clearing damaged cells to allow the regeneration of new, healthy ones. Although previous research has helped to build a clearer picture of how molecular biology aspects of autophagy works, some basic biophysics-related questions still remain to be answered. To tackle some of these questions, our interdisciplinary project will bring together mathematical modeling, cell biology, biomaterials science and nanotechnology. Computational modeling will help predict double membrane behavior, biomaterials and nanotechnology will help engineer double membranes artificially -outside the cells-, and cell biology will resolve the biological components influential in double membrane behavior in the context of autophagy. An inter-disciplinary effort enables that this research problem is approached from different angles. This is very useful for complex problems such as the one we focus in this project.
In this project we aim to establish how cellular double lipid bilayer vesicles are formed and developed in response to interfacial contacts. As a model concept, we will focus on autophagy, a cellular process that involves elimination of cytoplasmic objects in a double membrane compartment. At a molecular level, the mechanisms leading to the double bilayer vesicles in authophagy are well established, however, the striking membrane transformations have been largely overlooked at the mesoscale, the scale between atoms and cells. In order to address this knowledge gap, we have assembled a team consisting of a world leading molecular cell biologist, two talented early career scientists in applied mathematics and in lipid membrane nanotechnology, as well as state-of-the-art light and electron microscopists. Our approach is to identify and extract key molecules with molecular cell biology, and combine them with model membrane systems to observe isolated effects of the components. The data will be utilized to establish mathematical models which are essential to overcome the technical experimental limitations and to fully characterize the mechanisms involved. Our team previously worked in a thematically unrelated interdisciplinary project and jointly made several breakthroughs reported in some of the most prestigious scientific journals. Our synergy and experience in successfully implementing interdisciplinary research will be beneficial for the proposed project and we are confident that the project will lead to a paradigm change in the understanding of membrane dynamics during the autophagic process. Interference in the autophagy pathway has revolutionary therapeutic potential and we anticipate that some of our results will be relevant for understanding of diseases in which autophagy plays a key role as well as of the understanding of other cellular double membrane structures such as the nuclear envelope, mitochondria, chloroplasts and virus-induced double bilayer vesicles.
