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Biochemical and mechanochemical mechanisms in polarized cells

Periodic Reporting for period 2 - BIOPOL (Biochemical and mechanochemical mechanisms in polarized cells)

Reporting period: 2017-01-01 to 2018-12-31

BIOPOL is dedicated to the training of early stage researchers in the area of modern mechanobiology. Currently, it is still an open question how the physical environment is regulating cellular behaviour, moreover it is also largely unclear how the physical properties of cells contribute to cellular events like migration or tissue formation. For a long time the focus in molecular cell biology was preferentially on establishing protein/protein or protein/lipid interaction networks and signalling cascades, however it became clear that chemical signalling in the classical sense is insufficient to describe and mechanistically explain phenomena like tissue formation and cell differentiation and that the specific physical nature of the cellular environment as well as the intrinsic cellular physical properties have to be taken into account.
A rational approach to treat human diseases is incomplete without including mechanobiological aspects. Thus it is crucial that we establish a clear understanding of the mechanical cues governing cellular behaviour to exploit this knowledge for novel strategies of disease treatment, and tissue engineering in the future. BIOPOL aims to understand how mechanical cues are recognised by the cell and how these signals are translated into biochemical signalling and vice versa. BIOPOL aims in particular to elucidate the role of the plasma membrane, the lipid membrane, which surrounds each cell, in sensing the environment. The plasma membrane also plays an important role in regulating selective uptake of cargo via a mechanism called endocytosis. BIOPOL investigates how the physical properties of the plasma membrane influences endocytosis. Furthermore, BIOPOL analyses the role of mechanochemical signalling in establishing and maintaining cellular asymmetries and how this is translated into tissue formation in vivo.
Conclusions: Overall BIOPOL has provided state of the art training in the field of mechanobiology for 15 BIOPOL-fellows. Training was also widened to non-BIOPOL students by organising an open summer school on the topic of mechanobiology. In addition BIOPOL fellows have received significant transferable skill trainings in particular in the areas of scientific communication, entrepreneurship and career development. Extensive secondments of fellows between the consortium participants have led to fruitful scientific collaborations and several joint scientific publications are predicted to be the result. Scientific advances have been made in understanding mechanisms of cellular and molecular mechanosensing, and mechanotransductions. Furthermore, BIOPOL has performed a substantial number of outreach activities (over 30 events) helping to promote the significance of joint European research and the field of mechanobiology in particular.
BIOPOL has successfully hired fifteen early stage researchers (ESRs). These fifteen early stage researchers are enrolled into local PhD programs and each ESR is working on a particular clearly defined research project. After all fellows had been hired a fellow own meeting was organised by the fellows themselves with the support of the BIOPOL management in Rome, Italy.
The annual meeting of BIOPOL was held in Barcelona, Spain and was organised together with the Spanish network of excellence in mechanobiology. BIOPOL principal investigators and fellows gave scientific presentations. The first annual meeting was combined with a first workshop on scientific communications for the BIOPOL fellows. Workshop II with the topic “Project management and innovation” was held in February 2017 in Berlin, Germany. Fellows also participated in the BIOYES business plan competition in autumn of 2017. As a major training event BIOPOL organised an international open summer school on the topic “Mechanobiology of polarised cells”. The summer school took place at the ” Ecole de Physique” in Les Houches, France in April 2018.
Workshop III on the topic of entrepreneurship was delivered as a two-days webinar. The final workshop (workshop IV) on career development was delivered in September 2018. The workshop took place in Harrogate, UK , where also the final scientific meeting of BIOPOL was held. The final meeting “Physics of Cells: From Biochemical to Mechanical” comprised also a BIOPOL only satellite meeting open to all conference attendees. All abstracts are published in a conference book. In addition to these main training events, BIOPOL fellows have performed a set of experimental training stations and multiple secondments to other consortium members.
Overview of results and dissemination: Scientific advances have been made in particular in understanding mechanisms of mechanosensing (of cilia, caveolae, and mechanosensitive ion channels) and of mechanotransduction (YAP, actin cytoskeleton) as well as in mechanics of endocytosis and tissue formation (drosophila wing). Scientific results have been disseminated at scientific conferences in form of posters or scientific oral presentations, each of the fellows has presented their scientific results at at least one international conference, but in most cases fellows attended three and more conferences in total. Furthermore, each of the fellows has performed a minimum of one outreach activity (open day, scientific fairs etc.) per year, where different audiences (children, adults) of the general public were informed about BIOPOL’s mission and about research results so far achieved. Part of the scientific results have been exploited already in the form of scientific publications, and additional publications are in preparation or planned. JPK and MIMETAS have exploited their research results by implementation of new product software and improved OrganoPlate design and functionality, respectively.
Currently, we have several research publications with BIOPOL participation representing progress beyond the state of the art in the field of cell volume measurement, microfluidic based 3D cell culture systems, mechanics of clathrin mediated endocytosis, and deep learning based drug toxicity screening. The novel method to measure cell volumes allows the measurement of the volume of single cells. BIOPOL has also contributed to the development of a novel 3D cell culture system for gut epithelial cells, which can be exploited for drug screening. Furthermore, BIOPOL has shed insight into the role of the of clathrin light chain in regulating clathrin-mediated endocytosis of G-protein coupled receptors This is of major importance as a large number of currently available drugs are targeting this diverse receptor class and their endocytosis is intimately connected with their signalling capacity. Finally, BIOPOL has also contributed to extend the state of the art in the field of drug screening by developing a novel deep learning-based nuclei profiling tool for drug toxicity screening.
BIOPOL fellows have also participated in over 35 outreach activities including open days and scientific fairs aiming mostly at the general public (children and adults) emphasising the importance of research in general and the research topics of BIOPOL in particular. The direct and personal engagement with the general public will impact on the general acceptance of basic and translational research as important drivers for progress in the areas of health and economy.