Glycocalyx Engineering to Probe Mucin Signal Transduction

With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Professor Jessica Kramer of the University of Utah is studying the development of cellular glycocalyx models to understand processes that regulate cell growth and survival. The glycocalyx is a protein and sugar coating on the surface of cells. In locations such as the eyes, lungs, gastrointestinal and reproductive tract, the glycocalyx is rich in mucin proteins, which are also found in mucus. The mucin glycocalyx has complex biological functions and diverse roles in health and disease but has not been systematically studied at the chemical level. Through the course of this project, the PI seeks to create chemically tunable models of the glycocalyx and apply them to study cellular pathways essential for life. This pursuit allows graduate and undergraduate students to acquire specialized training in sugar and protein chemistry, as well as cell biology. This project is also integrated into an outreach program adaptable for K-12 students to learn about the building blocks of life. Mucin glycoproteins are crucial for life but challenging to study due to their inherent chemical heterogeneity. These rigid proteins span the cell membrane and perform complex biological functions on both the extracellular and cytosolic sides of the bilayer. During this project, the PI will employ chemoenzymatic techniques to synthesize a series of chemically and mechanically tunable mucin glycodomains. These synthetic mucins will be used to engineer the glycocalyx of live cells by attaching the synthetic glycodomains to their surfaces through a combination of genetic engineering and chemical conjugation. This approach seeks to enable a systematic investigation of mucin glycocalyx-mediated cellular signaling functions both intra- and extracellularly. The PI will utilize their glycocalyx model to explore how glycan-mediated clustering initiates biochemical signaling and the role of mucins in regulating cell extrusion events that maintain epithelial homeostasis. The ultimate objective of this research is to develop tools for studying the glycocalyx and to contribute to the understanding of its fundamental biochemical and biophysical roles. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.