BIOMUC - Mucin binding to bioactive molecules: physiological role and new biomaterials

Fiche  technique du Projet

• Programme de financement: 7e PCRD – programme Personnes  – Marie Curie Actions – International Outgoing Fellowships (IOF)
• Coordinateur: Université Claude Bernard Lyon 1, Prof. Laurent David
• Budget Total: € 280.017,60
• Subvention : € 280.017,60
• Durée : 01/04/2012-31/03/2015

Context / Contexte

Mucins are a family of glycoproteins that are found in animals as hydrated gels called mucus. In mammals, the moist epithelial layers synthesize mucins both in membrane-associated and in freely secreted form. This socalled “mucosal layer” covers the respiratory, gastrointestinal, and genital tracts, as well as the corneal surface. These mucosal layers have the challenging task to maintain a strong barrier towards potentially deleterious agents such as toxins and pathogenic microbes and viruses, while remaining permeable towards, gas, nutrients, and sperm cells, and allowing transparency towards light. Mucins are also highly hydrated molecules and provide exceptional mechanical1 and lubricating properties, which protect the underlying cells against dehydration as well as shear stresses induced by indigested food particles or invading pathogens.
The exceptional selective filtering property observed for mucin gels led many to study its interactions with various kinds of objects such as viruses and bacteria. Recently, more insight on the mechanisms of these interactions was gained. The decrease in diffusivity of certain objects is not only do to mucin mesh size (~ 300 nm) but also due to electrostatic interactions, as well as a range of other molecular interactions. This has been shown on small particles of controlled surface chemistry, but it is thought to be applicable to smaller objects such as biomacromolecules.

Objectives / objectifs

This project is expected to improve the understanding of the role of mucins, both in the context of its physiological roles as well as its potential as a building block for new biomaterials. For a long time, mucins have been considered as simple passive barriers on the epithelial lining, rejecting exogenous particles by size exclusion. The project will investigate whether mucins can also be a smart reservoir for bioactive molecules, thus actively influencing cell microenvironment perhaps promoting cell growth or differentiation. Although some clues exist in the literature, this has, up to our knowledge, never been studied before.
In close connection with this idea, this proposal also aims to develop the use of mucins as new components for bioactive biomaterials. Biomaterials based on natural products have the advantage of being environmentally friendly, i.e. they do not require toxic chemistry for their synthesis as their processing takes place in water, in mild conditions. They are becoming increasingly available and well defined, and most importantly can partly recreate the very complex microenvironment of cells, which is still too complex to be recreated completely de novo. Mucins are a completely untapped source for new biomaterials. Only one group has started looking at mucin-based multilayer films, and out of the context of drug delivery. Also, there is no previous work concerning hydrogels for tissue engineering comprising mucin. The behavior of standard fibroblast on mucin coatings is not known, which is the very first step for a new biomaterial coating. In particular there is no characterization of the adhesion, the spreading and migration of these cells. As knowledge increases on the biophysical properties of mucin as well as on their biology, it is becoming clearer that mucins have complex physiological roles, and can probably be engineered in very innovative biomaterials.

Impact/ results – Impact/résultats

Worldwide, a limited number of research groups are focusing on mucins in the context of biomaterials, and even less have the ability to purify mucins rather than using the less reliable commercial mucins. The fellowship will allow the reintegration in the ERA zone of a researcher with experience in mucin purification that is rare in France and Europe at this time. At the local level, the “Ingénierie des Matériaux Polymères” laboratory is focused on polysaccharide polymers, and has great expertise in the synthesis and characterization of glycosaminoglycans. A biomaterial group is emerging within the laboratory and return of the researcher in this group will bring an innovative approach and decisive skills for the conceptualization, development and valorization of mucin-based oligomers, coatings, nanoparticles, and complex hydrogels for a variety of biomedical applications. The multidisciplinary aspect of the project, implying chemistry, physico-chemistry of natural polymers, together with cellular and tissue biology and biomaterial evaluation, will greatly reinforce, strengthen and renew the activities of the "Polymer Materials for Life Sciences Group" at IMP.
Overall, this fellowship will allow a highly innovative research to be started in the United States, and brought back in the ERA. A large set of skills and knowledge will be brought back to the ERA and will also greatly benefit the development of the return host.

Le rôle de LIP 

LIP a accompagné le porteur de projet dans toute la phase de montage et de mise en place du contrat avec la Commission Européenne.