In research area A, we focus on the physico-chemical characterization and interpretation of the hydrogel properties of native mucus and mucin-mimicking synthetic hydrogels. The overall aim is to gain a better understanding of biological function and dysfunction of the mucus hydrogel based on its molecular architecture and mesoscopic structure and dynamics. For that purpose, the hydrogel will be systematically modified; in a topdown approach starting from healthy mucus, modifying its mucin composition in a controlled way via overexpression and knockout models, and comparing to mucus in the disease state; and in a bottom-up approach by synthesizing hydrogels of different complexity, which contain well-defined molecular features in order to see how they relate to the hydrogel properties.

• Project A01| Mall/Gradzielski: Hydrogel properties on airway surfaces in health and muco-obstructive lung disease

• Project A02| Gradzielski/Netz: Rheology and mesoscopic structure-dynamics relations of hydrogels

• Project A03| Netz/Block:Probing and modeling of transport properties of hydrogels

• Project A04| Alexiev/Seitz:Development and application of nanoviscosity probes in advanced FLIM studies on synthetic and native hydrogels in vitro

• Project A05| Hedtrich: Mapping the interdependency of the gut-lung-axis and hydrogel barrier in health and disease

Research area A is based on an integrated approach to study in particular the viscoelastic and transport properties of these systematically varied hydrogels in a comprehensive fashion. This means to cover an extended frequency range of the viscoelastic properties by a combination of micro- and macro-rheology, including studies of these properties as a function of the size scale, going from the nm range to the bulk property. The studies are complemented by a characterization of structure and dynamics over length scales from nm to many μm, thereby covering the complete size range of relevance. To achieve this aim we will combine the expertise of the project partners which constitute the experimental basis for developing theoretical models to describe the properties of the hydrogels of different complexity, starting from rather simplified model networks and working the way up to increasingly complex hydrogels, thereby approaching the biological situation. This is possible through a close interdisciplinary collaboration between experimental, theoretical and physician scientists starting with established model systems and employing state-of-the-art characterization and modelling methods. The insights gained in project area A thus set the basis for the areas B and C with the aim of developing mucin-mimicking systems further, first as new model systems, but then also to counteract native mucus dysfunction in disease states as a potential therapeutic strategy.