The cellular environment is heterogeneous. Some intracellular domains are now thought to arise due to weak attractive interactions between lipids, proteins and nucleic acids, leading to emergent domains much larger than individual components. Such phase-like behavior has been implicated in a range of processes from synapse structure, to signal transduction and transcriptional regulation. While it is appealing to speculate that these domains play a role in integrating signals and other cellular information, we cannot presently formulate the precise contributions these domains make to function. My group seeks to understand the new physical and biological principles that determine function in the gap in scale between all-atom molecular dynamics and established coarse-grained systems biology approaches. We will seek to understand the thermodynamics and physical underpinnings of domains in the cellular environment. We will build minimal models for domain forming membranes interacting with cytoplasmic droplets, motivated by synapses, and the diverse signaling platforms which often involve partitioning and localization of both membrane bound and cytoplasmic factors in close proximity. To this end we will use and extend the established theory of wetting transitions, which has mostly been developed in the context of solid homogeneous surfaces, and we will connect our theoretical predictions to experiments being performed by collaborator Veatch?s laboratory, and to other results in the literature. We will also investigate the ramifications of the high dimensionality of the space of protein and lipid abundances for phase behavior in cells, seeking strategies cells could use to navigate this space, and making predictions that can be verified with lipidomics and proximity labeling techniques. We will also investigate how driving from active cellular components can alter domain forming behavior. We will also investigate how thermodynamically driven domain can shape biological function at the level of individual proteins and interaction networks, combining established thermodynamic simulation techniques with non-equilibrium kinetic networks. We will investigate how the presence of domains can alter the function of established interaction motifs as well as strategies that explicitly depend on the propensity of the cellular environment to phase separate. We will quantify how domains could aid in the amplification and distribution of small signals and investigate whether domain formation could act as an effective analogue to digital converter. We will apply these ideas to the regulation of ion channels by membrane domains, especially in synapses, comparing with experiments in progress by Veatch. These projects will be significant in that they will provide deep insight into the role that phase behavior plays in determining cellular heterogeneity and in shaping function. The proposed work will have broad impacts for many researchers seeking to navigate a rapidly expanding field.

Public Health Relevance

The proposed research is relevant to the part of NIGMS?s mission seeking fundamental knowledge relevant to treating human disease because it will investigate the physical basis and functional consequences of phase separated domains in the membrane and cytoplasm. Understanding these domains could transform our understanding of neurodegenerative and other diseases which often involve pathological aggregation and other aberrant domain formation. It could also transform our understanding of a wide variety of drugs and treatments including alcohol and some anesthetics which alter domain formation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1)
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Lyster, Peter
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Yale University
Schools of Arts and Sciences
New Haven
United States
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