Project description
The dynamics of mucus formation
Mucus is a water-based, gel-like substance that coats and protects epithelial surfaces in the lungs, intestine and other organs. It consists primarily of large glycoproteins and acts as a barrier against pathogens, while also maintaining tissue hydration. However, the molecular principles that allow mucus to assemble into dynamic, functional hydrogels remain poorly understood. The ERC-funded MOLECULAR MUCUS project aims to investigate how the glycosylated regions of mucin proteins interact to form diverse 3D structures and hydrogels. Given that most glycosylation processes take place in the Golgi apparatus within cells, the project will unveil the role of this organelle in influencing mucus properties. Ultimately, project findings will help researchers manipulate mucus hydrogels to treat inflammatory and infectious diseases.
Objective
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.
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 test the hypothesis that glycosylated mucin regions are tunable entropic spacers that influence the positioning and adhesion of neighboring folded domains, thereby controlling mucin assembly and hydrogel formation. We will solve the first high-resolution structures of respiratory mucins and will develop an experimental and theoretical framework for analyzing the spans and dynamics of O-glycosylated mucin domains.
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, with potential implications for mucus biophysics and viral penetration. We will explore the benefits of this regulatory pathway for mucin self-assembly, hydrogel properties, and 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.
Fields of science (EuroSciVoc)
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2022-ADG
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7610001 Rehovot
Israel
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