Friday, May 9, 2025
5/9/2025
Functional Roles of the Membrane Phase Transition in Cellular Physiology - PROJECT SUMMARY The plasma membrane dictates how cells sense and respond to their environment, informing cellular decisions to, for example, proliferate, mature into other cell types, respond to pathogens, transmit electrical signals, or strengthen neuronal connections in the brain. Lipids and proteins within membranes act collectively to provide both a physical barrier to the extracellular space and the ability to selectively transmit information and materials to the cell. Defects in these processes lead to diverse human diseases ranging from cancer to immunodeficiency to neurodegeneration. Work in the PI’s lab seeks to discover how collective behaviors of membranes contribute to cellular sensing, combining physically rigorous thermodynamic models with single-molecule, supper-resolution fluorescence imaging and functional studies of signaling outcomes. The plasma membrane undergoes a liquid-liquid phase transition, and recent work from the PIs lab demonstrates that this phase transition enables membranes to adapt their compositions locally in response to external stimuli, establishing a heterogeneous environment that can impact membrane biochemistry to induce or modulate a functional response. Future work will explore the ways in which this highly susceptible membrane state shapes the functional outcomes of cell sensing, focusing on signaling systems relevant to immune recognition and on the functioning of individual ion channel receptors found at inhibitory synapses within neurons. Work in immune cells will explore the roles of membranes in regulating the biochemical networks responsible for sensing in these cell types, exploring the impact of receptor clustering, lipid homeostasis, and protein scaffolds such as cortical actin and condensed platforms of adaptor proteins that often assemble at membranes as part of signaling cascades. Work with ion channels will probe impacts of the membrane phase transition on the functioning of single proteins, exploring theoretical predictions of allosteric regulation by membranes and the chemical availability of hydrophobic effectors of channel activation. Future research will also begin to probe internal membranes, such the nuclear envelope, extending methods established in the PI’s lab to determine if and/or how these membranes exploit consequences of the phase transition. Through discovery of underlying mechanisms, the overall vision of the research program is to identify new approaches to influence cell sensing through manipulations of membrane properties, informing new strategies for the treatment of human disease.
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