alphaVbeta1 integrin: Analyzing the hidden master of fibrosis

• Applicant: Dr. Michael Bachmann
• Subject Area: Cell Biology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 403724929

We are all depending on efficient wound healing throughout our live. However, a scar remains. While the formation of a scar is important to fully heal wounds, it comes at the prize of lost tissue functionality. For example, scar tissue heals the heart after an infarct, but the scar tissue does not beat, no hair grows on scarred skin, and scars in a lung do not contribute to gas exchange. If the size of the scar exceeds a certain size, it interferes with proper organ function and leads to organ failure. Such a pathogenic progression is called fibrosis. Fibrosis is attributed to more than 40% of all death in the developed world. Obesity is an additional risk factor for fibrosis. With increasing number of obese people it is likely that the number of fibrosis-associated deaths will increase during the next years. Traditionally, fibrosis is named differently for every organ, masking the common features it shares in all tissues. At the onset of fibrosis is the transformation of cells into myofibroblasts that secrete increased amounts of extracellular matrix (ECM) proteins that close the wound and eventually form the scar. The master regulator of this transformation are transforming growth factor beta (TGFbeta) cytokines. TGFbeta is present in the ECM as an inactive LAP-TGFbeta complex. Binding of integrins, important cell-matrix adhesion receptors, to the complex releases TGFbeta. In the past, alphaV-integrins were assumed to be relevant in this process. Recent work suggests, however, that only alphaVbeta1 integrin is responsible for TGFbeta release in physiological settings. Unfortunately, alphaVbeta1 was so far rarely analysed by the research community because of technical challenges. Both parts of the integrin heterodimer associate with many other subunits thereby masking the alphaVbeta1 in the crowd of other integrins. Here, I will establish alphaVbeta1-specific substrates to address this problem by “taking this integrin out of the crowd”. Specifically, I will analyze the ligand preference of alphaVbeta1 to produce binary choice substrates. With this technique, recently established during my PhD, alphaVbeta1 will be physically separated from other integrins due to their differential ligand affinities. By this approach, alphaVbeta1 will be made available for various microscopic and physiological techniques, allowing its in-depth characterization. Using these binary choice substrates with single-particle tracking will give me the unique ability to study dynamics and conformation-specific regulation of alphaVbeta1 in a cellular setting. Moreover, this combination of advanced microscopy and unique substrate functionalization will yield an analysis platform that is suitable for any cell adhesion receptors. By reaching these goals, I will improve the understanding at the same time of alphaVbeta1 and fibrosis. This will offer multiple new possibilities for pharmacological interference with this master regulator of fibrosis.

• DFG Programme: Research Fellowships
• International Connection: Switzerland
• Host: Professor Dr. Bernhard Wehrle-Haller