Grant: Discovery Launch Supplement

Within eukaryotic cells, the spatial organization of metabolic processes relies upon the formation and maintenance of distinct internal compartments, called organelles, which are separated from one another by membranes. Throughout the variety of subcellular organelles, unique molecular classes of glycerophospholipids (GPLs) are the most abundant structural components and thus disproportionately influence bulk membrane properties. However, despite their essential functions, few research groups have been able to study the complex regulation of GPL turnover and transport. Consequently, the long-term goal of my research program is to define the molecular mechanisms that maintain functionally-distinct organellar membranes with characteristic GPL compositions. My laboratory will specifically exploit powerful new approaches that use induced proximity of engineered lipid-modifying enzymes to acutely alter the abundance and turnover of specific classes of GPLs within organelle membranes. These studies will train a diverse group of highly-qualified personnel (HQP) to use a contemporary suite of cell biology methods, including molecular engineering, structural bioinformatics, unbiased metabolomics, and advanced imaging modalities. Importantly, these opportunities to pursue impactful basic research questions using innovative experimental techniques will prepare HQP to become future leaders in the emerging field of molecular membrane biology. Within this long-term research program, my laboratory will pursue the following short-term objectives over the next 5 years: Objective 1: Characterize the spatial organization and kinetic flux of metabolic intermediates essential for GPL biosynthesis. Newly-established molecular tools capable of selectively manipulating the relative abundance of essential GPL precursors within specific organelle membranes will be used to define the metabolic channeling of these important synthetic intermediates. Objective 2: Investigate the relationship between membrane GPL composition and the regulation of organelle-selective membrane remodeling and quality control. Engineered lipid-modifying enzymes will be used to investigate the direct impacts of acute changes to the local membrane composition on organelle morphology and membrane-associated protein functions. Objective 3: Identify novel molecular machineries responsible for the localized turnover and inter-organelle transport of GPLs. High-throughput biophysical screening methods that use organelle-specific lipid biosensors will be introduced to identify proteins that impact the localized turnover of unique GPL species. Overall, in leveraging these complementary approaches, my research group will be among an elite cohort worldwide that can reach physiologically relevant conclusions regarding how the dynamic regulation of organelle membrane homeostasis is spatially organized and directly influences the integrative metabolic processes that ultimately dictate cellular functions.