Physical Biology of the Cellular Glycocalyx

University Of California At Davis, Davis CA

Investigators

Abstract

Project Summary/Abstract All cells in the body are covered with a sugar- and protein-rich material called the glycocalyx. Specific changes to the composition and organization of the glycocalyx are linked to lethal cancers and other debilitating diseases, but the mechanisms are not fully understood. Our group’s mission is to uncover the physical principles that define glycocalyx function with the hope that we can reprogram cells back to normal, healthy states or other desired phenotypes through rational manipulation of the glycocalyx. An interwoven mission is to develop the infrastructure—custom-tailored experimental tools and computational models—necessary to propel the early stages of biophysical inquiry in glycobiology. Our proposal will develop imaging tools intended to resolve the nanoscale architecture of the glycocalyx and probe its physical properties. We will continue to advance a systematic approach for engineering the biochemical and biophysical states of the glycocalyx through genetic methods. Theoretical models will be constructed to understand structure-function relationships for the glycocalyx. The tools and models that we develop for glycocalyx research will be applied to understand how the glycocalyx physically regulates various modes of intercellular communication, including through cell-surface receptors, highly curved membrane structures, and extracellular vesicles. Cell surface receptors reside and operate within the densely crowded glycocalyx. We will test the specific hypothesis that entropic forces arising from macromolecular crowding in the glycocalyx can strongly influence receptor assembly and activation. We will initially consider the effects of glycocalyx crowding on the dynamics and activation of growth factor receptors, including the epidermal growth factor receptor family. Works from our group have implicated transmembrane mucins and other membrane-anchored polymers in the glycocalyx as membrane curvature generating machines. Here, we will investigate how membrane-bending by the glycocalyx can support the projection of microvilli and the secretion of extracellular vesicles that bud from the plasma membrane and tips of microvilli. We will consider whether the residual glycocalyx on vesicles controls vesicle stability, fusogenic properties, and communication, including through the glycan epitopes that the vesicles carry. Our overarching hypothesis is that the biophysical properties of the glycocalyx play key roles in the transmission and receipt of biological information to and from cells. Emerging from our hypotheses is a vision that glycocalyx engineering and pharmacological targeting of the glycocalyx represent viable strategies to harness control over cellular interactions in tissue engineering, regenerative medicine, and cell-based therapeutics. Insights from our work are intended to inform the development of therapeutic strategies that can correct the broken channels of intercellular communication that are ubiquitous in diseases such as cancer.