Molecular Mechanisms for Construction of Protective Mucus Hydrogels

Projektbeschreibung

Die Dynamik bei der Schleimbildung

Schleim ist eine wasserbasierte, gelartige Substanz, die Epitheloberflächen in Lunge, Darm und anderen Organen auskleidet und schützt. Sie besteht hauptsächlich aus großen Glykoproteinen und dient als Barriere gegen Krankheitserreger, während sie gleichzeitig die Gewebehydratation aufrechterhält. Die molekularen Prinzipien, die es dem Schleim ermöglichen, sich zu dynamischen, funktionellen Hydrogelen zusammenzusetzen, sind jedoch noch unzureichend verstanden. Im Rahmen des ERC-finanzierten Projekts MOLECULAR MUCUS soll untersucht werden, wie die glykosylierten Regionen von Mucinproteinen interagieren, um verschiedene 3D-Strukturen und Hydrogele zu bilden. Da die meisten Glykosylierungsprozesse im Golgi-Apparat im Inneren der Zellen ablaufen, wird das Projekt die Rolle dieser Organelle bei der Beeinflussung der Schleimeigenschaften aufdecken. Letztendlich werden die Projektergebnisse den Forschenden helfen, Schleimhydrogele zu manipulieren, um Entzündungs- und Infektionskrankheiten zu behandeln.

Ziel

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.