In this project, the PI will develop new tools for interrogating lipid function and apply them to understanding how organization emerges in biological systems. Cells and their internal organelles are compartmentalized by thin sheets of lipid molecules called membranes, which serve as the environment for a range of molecular processes. The chemical composition of these membranes controls their properties, is mediated by diet, and can be genetically altered. Understanding how lipid composition impacts cellular processes is thus of broad importance. The project’s research will test how specific lipid-lipid interactions drive the formation of membrane domains and cellular transport networks. The PI will integrate research systems into an outreach program to improve high school education in quantitative STEM fields such as physics, which is currently lagging in many segments of the American population. For this, learning modules will be developed that harness processes occurring in cell membranes to teach physics concepts through biological applications. The ability of this approach to promote physics and quantitative biology will be tested in San Diego-area schools that primarily serves an underrepresented minority (URM) student population.

The goal of the project is to translate models of membrane organization from synthetic models to real cell membranes, where their biological roles can be evaluated. The project’s research aims harness two eukaryotic organelles that display micron-scale lateral phase separation: the yeast vacuole, which patterns into ordered membrane domains that act as catabolic docking sites upon diet restriction, and the mammalian Golgi, in which similar domains could act as sites of secretory cargo sorting. For each compartment, methods for the quantitative manipulation of domain-forming lipid stoichiometry will be developed using metabolic engineering strategies. This approach will allow characterization of membrane phase properties in living cells and elucidation of how they modulate function. Findings will then be harnessed to 1) explore the function of lipid head-group modifications in domain formation and 2) reconstruct pathways for the diversification of sterol structure during eukaryotic evolution. In parallel, an integrative educational component will be developed that uses cell membranes as an instructional system to integrate concepts in the quantitative sciences with biological applications for high schoolers. The new Lesson Study model-based education program for San Diego-area high school teachers will increase training in the quantitative sciences by URM students and provide continuing in-person mentorship by project personnel.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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Jaroslaw Majewski
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University of California San Diego
La Jolla
United States
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