Inflammatory bowel disease (IBD), conferring a dramatically increased risk for development of colorectal cancer (CRC), results from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host. However, the exact etiology of IBD is unknown. Building up on high impact papers from the host group reporting on the recently discovered innate lymphoid cells (ILCs) as key players in mucosal inflammation, I now aim to unravel the role for ILCs in IBD and CRC. Interestingly, while the IL-22 producing ILC3 seem to be crucial in maintaining intestinal homeostasis, the IL-17 and IFN-gamma-producing ILCs can cause inflammation in a mouse model of colitis and are present in human IBD. Furthermore, ILCs were recently described to be involved in modulating immune responses, by interacting with CD4+ T cells and mononuclear phagocytes in the mouse intestine. I aim to identify critical pathways in the crosstalk of ILC3 with other immune cells in the human intestine. The ultimate purpose is to assess how these interactions affect immune homeostasis and disease progression in IBD and CRC. We will pinpoint crucial interaction molecules and cellular processes that can be used for monitoring current therapies as well as finding new therapy targets for IBD and CRC. This truly translational proposal utilizes, in an optimal manner, unique state-of-the-art techniques and patient materials to provide novel insights into the etiology of IBD and CRC. The excellent track record of the hosting group, the highly suitable infrastructure provided by the host institution and my own extensive research experience ensures a high degree of feasibility. Furthermore, this project provides excellent training opportunities, skill advancement possibilities and career prospects for me and its results are expected to have a direct impact on the European society.

To change human diets is an urgent global health and sustainability goal; yet, overcoming preferences for familiar food flavors in favor of healthier or more sustainable options remains a major challenge. Odor-taste associative learning is the principal perceptual support process for flavor preference formation and retrieval. Mechanistic insight into the cortical processes that transfer appetitive properties of an odor from the mouth onto environmental objects is, however, almost completely absent. As a result, fundamental questions about the processes that drive the acquisition of new flavor preferences, and their regulation by signals from the digestive tract, still remain to be answered. OLFLINK will uncover processes that link olfactory perception inside and outside the mouth across three nested levels of investigation that are usually studied in separation. In doing so, I propose to discover key factors that facilitate or hinder acquisition of new flavor preferences. Specifically, I will 1: determine the distributed CODE by which odors acquire and evoke taste associations (WP1), 2: delineate the cortical CONTROL mechanisms that facilitate encoding and retrieval of odor-taste associations in the light of contextual variability (WP2), and 3: determine the interactions with digestive feedback that REGULATE this flexible coding system during flavor preference acquisition and retrieval (WP3). This final step especially provides insight into the body’s ability to adjust learning and retrieval of food preferences based on nutritional needs, and has potential to transform our thinking about the biological basis of maladaptive eating patterns. The novel insights from OLFLINK will fill the knowledge gap that currently exists between the mechanisms driving perceptual experiences during food consumption and the subsequent evaluation of food in the outside world, and will inspire the development of novel interventions to facilitate dietary changes over the life course.

Engineers in nanotechnology research labs have been quite innovative the last decade in designing nanoscale materials for medicine. However, very few of these exciting discoveries are translated to commercial medical products today. The main reasons for this are two inherent limitations of most nanomanufacture processes: scalability and reproducibility. There is too little knowledge on how well the unique properties associated with nanoparticles are maintained during their large-scale production while often poor reproducibility hinders their successful use. A key goal here is to utilize a nanomanufacture process famous for its scalability and reproducibility, flame aerosol reactors that produce at tons/hr commodity powders, and advance the knowledge for synthesis of complex nanoparticles and their direct integration in medical devices. Our aim is to develop the next generation of antibacterial medical devices to fight antimicrobial resistance, a highly understudied field. Antimicrobial resistance constitutes the most serious public health threat today with estimations to become the leading cause of human deaths in 30 years. We focus on flame direct nanoparticle deposition on substrates combining nanoparticle production and functional layer deposition in a single-step with close attention to product nanoparticle properties and device assembly, extending beyond the simple commodity powders of the past. Specific targets here are two devices; a) hybrid drug microneedle patch with photothermal nanoparticles to fight life-threatening skin infections from drug-resistant bacteria and b) smart nanocoatings on implants providing both osteogenic and self-triggered antibacterial properties. The engineering approach for the development of antibacterial devices will provide insight into the basic physicochemical principles to assist in commercialization while the outcome of this research will help the fight against antibiotic resistance improving the public health worldwide.

The enteric nervous system (ENS) contains a large range of neural subtypes that collectively controls essential gut functions independently of the central nervous system (CNS). Although the ENS is capable of forming new neurons following injury or inflammation, it fails to regenerate completely. My lab recently established a molecular classification of enteric neurons and discovered that they diversify through a conceptually new principle during development. Only two neuronal identities form during neurogenesis while all other classes emerge through subsequent differentiation at the postmitotic stage. This stepwise conversion process contrasts from the better understood CNS development where spatial patterning of stem cells predominates cell fate decisions. Dissecting the molecular basis for the sequential acquisition of cell identities in the ENS will advance our fundamental understanding of cell heterogeneity emergence. In divENSify we propose to push new frontiers in neuronal identity formation to facilitate constructive regeneration in the adult gut. Combining single cell RNA and chromatin profiling we will assess the role of pioneering transcription factors and competent cell states in each step of differentiation. We will dissect gene regulatory networks and identify key determinants using ultrasound-guided gene manipulation, a novel method we recently developed to target the otherwise inaccessible ENS in utero. We will determine how injury-induced adult neurogenesis correlates with developmental paradigms and leverage knowledge on latent potentials and intrinsic transcriptional regulators to engineer specific neuron types through viral gene manipulation in the adult gut. The proposed project will transform our comprehension of neuron identity formation and maintenance and provide proof-of-principle experiments that open for self-repair strategies to treat neurological gut disorders.