Molecular Mechanisms for Construction of Protective Mucus Hydrogels

Description du projet

La dynamique de la formation du mucus

Le mucus est une substance gélatineuse à base d’eau qui recouvre et protège les surfaces épithéliales des poumons, de l’intestin et d’autres organes. Il se compose principalement de grandes glycoprotéines et agit comme une barrière contre les agents pathogènes, tout en maintenant l’hydratation des tissus. Cependant, les principes moléculaires qui permettent au mucus de s’assembler en hydrogels dynamiques et fonctionnels restent mal compris. Le projet MOLECULAR MUCUS, financé par le CER, vise à étudier comment les régions glycosylées des protéines mucines interagissent pour former diverses structures 3D et des hydrogels. Étant donné que la plupart des processus de glycosylation ont lieu dans l’appareil de Golgi à l’intérieur des cellules, le projet dévoilera le rôle de cet organite dans l’influence des propriétés du mucus. À terme, les résultats du projet aideront les chercheurs à manipuler les hydrogels de mucus pour traiter les maladies inflammatoires et infectieuses.

Objectif

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.