Molecular Mechanisms for Construction of Protective Mucus Hydrogels

Introduction

Our bodies produce copious mucus daily to shield vulnerable epithelial cell surfaces in the lungs, intestines, and other organs. Mucus is crucial for defense against pathogens and other environmental hazards, but the mechanisms by which mucus hydrogels assemble and execute their functions are poorly understood. The main obstacle has been that the enormous, heavily glycosylated, and flexible mucin proteins constituting mucus are not readily amenable to structural and molecular approaches. However, I contend that mucin glycoproteins have exquisitely specific abilities and interactions that are ultimately understandable on the molecular level.

Research Plan

By carrying out the research plan described herein, we will crack the code that transforms the primary building blocks of mucins into diverse three-dimensional, dynamic, and active hydrogels. Specifically, we will:

1. Test the hypothesis that glycosylated mucin regions are tunable entropic spacers that influence the positioning and adhesion of neighboring folded domains.
2. Control mucin assembly and hydrogel formation.
3. Solve the first high-resolution structures of respiratory mucins.
4. Develop an experimental and theoretical framework for analyzing the spans and dynamics of O-glycosylated mucin domains.

Recent Discoveries

Perhaps most exciting is our recent discovery that the redox set-point of the Golgi apparatus influences sialic acid decoration of O-glycans during mucus biosynthesis. This has potential implications for mucus biophysics and viral penetration.

Future Directions

We will explore the benefits of this regulatory pathway for:

• Mucin self-assembly
• Hydrogel properties
• Mucus barrier function

Together, this work will pave the way toward rationally manipulating mucus hydrogels, offering new avenues for the treatment of inflammatory, fibrotic, and infectious diseases.