Cellular surfaces as regulators of biomolecular condensate assembly

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PROJECT SUMMARY. Introduction: Biomolecular condensates, composed of a concentrated network of proteins and nucleic acids, compartmentalize cellular biochemistry. The establishment of a precise molecular composition is critical for the biological functions of condensates. In particular, cells must assemble either (a) coexisting condensates of distinct composition within a shared environment or (b) coexisting sub-layers of distinct composition within the same condensate. In both cases, the mechanisms by which cells specify compositional identity are poorly understood. In this proposal, I will examine how two types of biological “surfaces,” (a) two-dimensional lipid membranes and (b) one-dimensional long noncoding RNA polymers, establish condensate identity and dictate the formation of distinct layers. I hypothesize that each type of surface regulates condensate composition and function by modifying RNA structure in distinct ways. Research: In Aim 1, I will examine how membrane surfaces modify RNA structure to control condensate identity and regulate mRNA translation in the cytoplasm. In Aim 2, I will examine how the structural features of a long noncoding RNA control the formation of condensates with discrete layers and regulate mRNA retention in the nucleus. The overall outcome will be an enhanced, mechanistic understanding of how cells assemble key compartments of mRNA function. Training: I will complete my training with Prof. Amy Gladfelter at UNC Chapel Hill. During the training period, I will work with innovative collaborators to acquire new skills that will enable me to probe and manipulate RNA structure and dissect the molecular driving forces of biomolecular condensation. These skillsets will accelerate discovery during the remainder of my training and form the foundation for my independent lab. Specifically, I will learn powerful strategies to (1) map RNA structure with Kevin Weeks at UNC; (2) study long noncoding RNAs with Mauro Calabrese at UNC; (3) examine the spatial regulation of mRNA translation with Chris Nicchitta at Duke University; and (4) develop mathematical models of biological self-assembly with Krishna Shrinivas at Harvard University. Environment: Prof. Gladfelter is a supportive and inspiring mentor who fosters creativity and collaboration. UNC Chapel Hill is a hub for world-class RNA biology and will provide valuable opportunities to learn from experienced scientists. This K99/R00 award will enable me to pursue exciting new research directions beyond my core skillsets, form strong collaborations with leading labs, and immerse myself in new disciplines through a variety of courses, seminars, workshops, and conferences. Impact on Public Health: The process of biomolecular condensation has generated intense interest in recent years, in part due to its role in the formation of pathological aggregates that cause neurodegenerative diseases such as amyotrophic lateral sclerosis. My work will uncover fundamental mechanisms by which cells control the composition and emergent functions of biomolecular condensates. Through these discoveries, I hope to aid in the development of clinical interventions to treat diseases caused by disruptions to this important cellular phenomenon.