Glycan-rich cell coats
Modelling mucin-like structures to analyse cell coat binding.
Background
A glycocalyx encompasses almost every cell in humans and is comprised of a negatively charged gel-like layer of sugars, anchored to the cell surface via lipids and proteins. Enveloped viruses that bud from surfaces of infected cells carry the glycosylation patterns of the host cell with them.
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The glycocalyx functions to protect the cell and to facilitate communications to and from the cell. Despite the ubiquitous presence of glycocalyx in human cells, many of the functions of the components remain elusive. It is important to understand how the structures within the glycocalyx interact with proteins.
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Impairment of endothelial glycocalyx has been linked to global health issues including atherosclerosis and obesity, diabetes complications and cardiovascular disease. Greater understanding of the glycocalyx role in cell capture under blood flow, mechanotransduction signaling and hemostasis would unveil novel therapeutic treatment routes for glycocalyx associated pathologies. Current work involves in vitro modelling of a simplified glycocalyx with microbes as white blood cell mimetic.
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Excessive salt in vasculature damages endothelial cells and underlying blood vessel tissue which contribute to cardiovascular related pathologies. The figure depicts the glycocalyx (blue) acting as a salt-buffer to prevent rapid Na+ absorption from plasma. Extensive sulfation of glycosaminoglycan (GAG) chains such as hyaluronan contribute to the negative charges that transiently bind Na+ in blood vessel lumens. Improving the endothelial glycocalyx homeostatic buffering capabilities would reduce atherosclerotic plaque formation and vasculature related pathologies.
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What are we doing?
Some of the most heavily researched elements of the glycocalyx have been highlighted in the schematic on the left. Proteoglycans, glycoproteins and hyaluronan make up a major component of the glycocalyx. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. Hyaluronan provides structural support. P-selectin mediates rolling of platelets and leukocytes on activated endothelial cells. After platelet activation, P-selectin is translocated from Weibel-Palade bodies to the external membrane. CD44 is highly expressed in many cancers and regulates metastasis. Gaining a greater understanding of the illusive glycocalyx requires interdisciplinary collaboration, combining biophysics, computational modelling and novel experimental techniques.
This project aims to build a glycocalyx model to understand its role in cell capture under the blood flow. Richter Labs have developed a novel glycocalyx model (right) including P-Selectin adhesion molecule and hyaluronan to analyse how blood cell mimetics interact with the vascular walls. Modelling the complex and dynamic glycocalyx environment has proves a challenge in research due to the huge in vivo variability. By selecting hyaluronan and P-selectin molecules we can gain further understanding of their contribution to cell capture.
Tools used within our research on glycan-rich cell coats
Click on each icon to learn more about the technique, and how it is used in our research
To visualise the binding interactions between the P-Selectin and white blood cell mimetic.
To understand more about interactions and forces between molecules within the glycocalyx.
To build a construct to mimic aspects of the in vivo environment.