Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and damage. This drives liver inflammation, promoting the progression to non-alcoholic steatohepatitis (NASH) and liver fibrosis. There are currently no approved therapies for NASH and fibrosis, which is in part due to a lack of knowledge of the immunological events underpinning NASH and fibrosis. The pathogenesis of NASH is strongly influenced by crosstalk with other tissues. There is increasing evidence that specifically obese adipose tissue macrophages (ATMs) are directly linked to liver pathology. In this respect, the host lab has shown that obese ATMs increase hepatic macrophage number. However, the exact changes in macrophage subsets and phenotypes were not investigated. I recently demonstrated that in NASH liver macrophages display large heterogeneity in phenotype and tissue localization and this plays a key role in NASH-associated liver fibrosis. Based on this combined preliminary data generated by the host lab and me, I hypothesize that ATMs alter hepatic macrophage composition and consequently affect the progression of NASH to liver fibrosis. By combining the mouse models and expertise available in the host lab and advanced technology present at the host institute, with my expertise in detailed immunophenotyping of the liver in NASH and fibrosis, I will address this innovative hypothesis in great detail. To bridge the translational gap from animal studies, I will investigate the potential contribution of ATMs to hepatic inflammation and fibrosis in humans by using unique fresh paired adipose tissue and liver biopsies available through the clinical network of the host lab. MacTalk integrates the scientific and technical expertise of both me and the host lab, creating a unique framework to identify novel mediators of hepatic inflammation and fibrosis. Furthermore, MacTalk will lay a strong foundation for my future career as independent researcher in the field of liver fibrosis.

Chronic kidney disease (CKD) results in loss of kidney function in patients, ultimately requiring organ transplant. Critical organ shortage and organ rejection after transplant make extended dialysis inevitable and the only therapy available. To exacerbate this problem, the incidence of CKD is increasing worldwide, with >14% of the general population affected. Hence, there is an urgent need for novel therapies. Induced pluripotent stem cells have been used to create kidney organoids representing early renal development stages. These organoids might be a suitable therapy in the future but fundamental challenges to achieve late stages of physiologically relevant maturation and function need to be addressed. The lack of vasculature and collection duct systems limits the viability and filtrate removal. To overcome this challenge, I aim to develop a novel, mature in vitro kidney model by exploiting different bioprinting technologies combined with organoid knowledge. This solution will include a bioengineered kidney extracellular (ECM) microenvironment, a vascularized network and a collecting duct system. I hypothesize that the strategic combinations of different bioprinting techniques will allow the development of key structures such as vasculature, essential for promoting maturation of the in vitro model, and a collecting duct for filtrate collection with an expected increase in function resembling the organ. Finally, the combination of the different modules on a microfluidic platform will allow the accurate control of the organoid perfusion and long-term cultures. NEPHRON will allow further knowledge on bioprinting functional kidney units while providing scientists an improved in vitro model to study development, disease and regeneration of the kidney. This knowledge can lead ultimately to alternative therapies and give initial indications on the future possibility of bioprinting a full functional organ.

Our brain processes multitudes of signals based on recurrent network activity involving feedforward and feedback interarea communication. To funnel information efficiently between areas, low-frequency rhythmic neural activity patterns couple to each other. It is an unresolved question how early sensory cortex (SC) can couple efficiently to both feedforward sensory information flow and feedback information flow arriving from higher order regions such as prefrontal cortex (PFC). Since PFC and sensory input lack direct coupling and operate with their own temporal dynamics, SC decouples from the sensory input when PFC couples to SC. It is therefore not possible to achieve efficient multi-area coupling in currently proposed feedback-driven coupling schemes. In search of a mechanism to address this problem I resort to a dynamical systems process called anticipated synchronization (AS). During AS, a receiving system (PFC) sends a copy of its own activity as delayed feedback to itself, allowing this system to - paradoxically - anticipate the dynamics of the driving system (SC). During AS, information from PFC is sent back to SC arriving at the right time in the future, while SC maintains sensory coupling. My goal in the next 5 years is to provide evidence of interarea AS coupling by creating a biophysical model of AS, empirically testing its predictions using ECoG data, psychophysics and EEG. By validating the use of tACS to control coupling, I will experimentally induce AS in a new closed-loop set-up that stimulates PFC with its own delayed activity. The proposed research will settle a critical theoretical debate on temporal coordination of interarea brain communication and will provide the computational basis for the hitherto unexplained excess of local feedback loops in the brain. The findings will inform new closed-loop treatment approaches and can improve biologically-inspired artificial intelligent systems that currently disregard the exact timing of information flow.