ERC FUNDED PROJECTS

Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.

2 325 292 €

Start date: 2018-06-01, End date: 2023-05-31

Spider silk is Nature’s high performance material that has the potential to revolutionize the materials industry. However, production and spinning of artificial spider silk fibers are challenging, and current methods to produce silk fibers include denaturing conditions which prevent the silk proteins from assembling into fibers in the same complex way as native silk proteins do. In order to fulfill the potential of spider silk we need to increase our understanding of the silk formation process and decipher how protein folding and interactions relate to mechanical properties of the resulting silk fiber. Recent insights into the physiology and molecular mechanisms of the spinning process has made it possible to develop a biomimetic artificial spider silk spinning device (see our publications Andersson et al. Nat Chem Biol. 2017; Otikovs et al. Angew Chemie Int Engl Ed. 2017). We are, for the first time, able to spin artificial silk fibers in which the proteins adopt correct secondary, tertiary and quaternary structures. The overall objective of ARTSILK is to build on these recent technical leaps and use state-of-the-art technologies to generate artificial silk fibers that are equal or superior to native spider silk in terms of toughness and tensile strength. To reach the overall objective we will use the recently mapped spider genome, protein engineering and single cell RNA (ScRNA) sequencing to design novel silk proteins for fiber production. We will also study the relationship between protein secondary structure formation and fiber mechanical properties in order to decipher the ques that determine mechanical properties of the fiber. This knowledge will be important also for the basic understanding of how soluble proteins covert into b-sheet rich fibrils in, e.g., Alzheimer’s disease. Finally, we will use microfluidic chips to engineer the next generation spinning device and 3D-printing techniques to make reproducible three-dimensional structures of spider silk.

2 000 000 €

Start date: 2019-05-01, End date: 2024-04-30

The role of experience in language acquisition has been the focus of heated theoretical debates, between proponents of nativist views according to whom experience plays a minimal role and advocates of empiricist positions holding that experience, be it linguistic, social or other, is sufficient to account for language acquisition. Despite more than a half century of dedicated research efforts, the problem is not solved. The present project brings a novel perspective to this debate, combining hitherto unconnected research in language acquisition with recent advances in the neurophysiology of hearing and speech processing. Specifically, it claims that prenatal experience with speech, which mainly consists of prosody due to the filtering effects of the womb, is what shapes the speech perception system, laying the foundations of subsequent language learning. Prosody is thus the cue that links genetically endowed predispositions present in the initial state with language experience. The proposal links the behavioral and neural levels, arguing that the hierarchy of the neural oscillations corresponds to a unique developmental chronology in human infants’ experience with speech and language. The project uses state-of-the-art brain imaging techniques, EEG & NIRS, with monolingual full term newborns, as well as full-term bilingual, preterm and deaf newborns to investigate the link between prenatal experience and subsequent language acquisition. It proposes to follow the developmental trajectories of these four populations from birth to 6 and 9 months of age.

1 621 250 €

Start date: 2018-06-01, End date: 2023-05-31

In BIORECAR I will develop a new breakthrough multifunctional biomaterial-based platform for myocardial regeneration after myocardial infarction, provided with biochemical cues able to enhance the direct reprogramming of human cardiac fibroblasts into functional cardiomyocytes. My expertise in bioartificial materials and biomimetic scaffolds and the versatile chemistry of polyurethanes will be the key elements to achieve a significant knowledge and technological advancement in cell reprogramming therapy, opening the way to the future translation of the therapy into the clinics. I will implement this advanced approach through the design of a novel 3D in vitro tissue-engineered model of human cardiac fibrotic tissue, as a tool for testing and validation, to maximise research efforts and reduce animal tests. I will adapt novel nanomedicine approaches I have recently developed for drug release to design innovative cell-friendly and efficient polyurethane nanoparticles for targeted reprogramming of cardiac fibroblasts. I will design an injectable bioartificial hydrogel based on a blend of a thermosensitive polyurethane and a natural component selected among a novel cell-secreted natural polymer mixture (“biomatrix”) recapitulating the complexity of cardiac extracellular matrix or one of its main protein constituents. Such multifunctional hydrogel will deliver in situ agents stimulating recruitment of cardiac fibroblasts together with the nanoparticles loaded with reprogramming therapeutics, and will provide biochemical signalling to stimulate efficient conversion of fibroblasts into mature cardiomyocytes. First-in-field biomaterials-based innovations introduced by BIORECAR will enable more effective regeneration of functional myocardial tissue respect to state-of-the art approaches. BIORECAR innovation is multidisciplinary in nature and will be accelerated towards future clinical translation through my clinical, scientific and industrial collaborations.

2 000 000 €

Start date: 2018-07-01, End date: 2023-06-30