Objectives of the CRC 1449

The overarching aim of this CRC is to understand the individual and combined contributions of the physicochemical key parameters to hydrogel (dys)function in health and disease. To achieve this goal, we will conduct detailed analyses (biophysical, biological and chemical) of native and synthetic hydrogels (mucus and glycocalyx) and focus on the role of hydrogel (dys)function in the context of diseases in which (abnormal) hydrogels/ mucus play a central role: i) cystic fibrosis (mucoviscidosis) as a chronic muco-obstructive lung disease triggered by abnormal viscoelastic properties of mucus in the airways, ii) acute respiratory tract infections caused by inhaled pathogens (bacteria and viruses), and iii) inflammatory bowel disease, a chronic disease condition associated with the mucus composition in the gastro-intestinal tract. Our key objective is the molecular definition of mucus (structure, properties and dynamics at the molecular level), which we base on a thorough and comprehensive physical characterization (mesh size, fibrillary structure, charge conditions, viscoelastic and transport properties) and our ability to synthetically prepare relevant components, which allows to probe hypotheses on a well-defined molecular level. Our chemical, physical, medical and modelling expertise will then be applied to specific key questions:

What is the role of the individual hydrogel components, i.e., mucins, proteins, salt and water, in the complex process of their network formation and function?

• Can we chemically and biophysically mimic native hydrogel properties by synthetic analogues and understand the dynamics of hydrogel formation?
• What are rheological and structural properties of hydrogels (mucus/glycocalyx) and how do they depend on the molecular composition?
• How do hydrogel (mucus/glycocalyx) properties change in the transition from a healthy to a disease state of increasing severity?
• Can disease states override the protective effect of the mucus barrier and what role does the glycocalyx play?
• How do the (native/synthetic) hydrogel barriers prevent infection by bacteria and viruses?
• What role does mucus play in the composition of the microbiota and vice versa?
• How can synthetic hydrogels or mucin modulators support the transition from disease to health and can this knowledge generate new preventive or therapeutic strategies?