Molecular Mechanisms for Construction of Protective Mucus Hydrogels

Descrizione del progetto

La dinamica della formazione del muco

Il muco è una sostanza a base acquosa, simile a un gel, che riveste e protegge le superfici epiteliali di polmoni, intestino e altri organi. È costituito principalmente da grandi glicoproteine e funge da barriera contro gli agenti patogeni, mantenendo al contempo l’idratazione dei tessuti. Tuttavia, i principi molecolari che permettono al muco di assemblarsi in idrogel dinamici e funzionali rimangono poco conosciuti. Il progetto MOLECULAR MUCUS, finanziato dal CER, mira a studiare come le regioni glicosilate delle proteine muciniche interagiscono per formare diverse strutture 3D e idrogel. Dato che la maggior parte dei processi di glicosilazione avviene nell’apparato di Golgi all’interno delle cellule, il progetto svelerà il ruolo di questo organello nell’influenzare le proprietà del muco. In definitiva, i risultati del progetto aiuteranno i ricercatori a manipolare gli idrogel di muco per trattare malattie infiammatorie e infettive.

Obiettivo

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.