Title Promoter Affiliations Abstract "Exploration of the ectophosphodiesterase NPP1 as a target for the treatment of calcification diseases." "Mathieu Bollen" "Skeletal Biology and Engineering Research Center, Laboratory of Biosignaling & Therapeutics" "The integral membrane protein NPP1 (Nucleotide Pyrophosphatase/Phosphodiesterase-1) generates PPi by the hydrolysis of extracellular ATP. PPi is an inhibitor of calcification in soft tissues and prevents the disproportionate accumulation of hydroxyapatite in bones. An excess of PPi results in the deposition of pathological calcium pyrophosphate dihydrate crystals (chondrocalcinosis), but also contributes to the development of hypophosphatasia, which is characterized by poorly mineralized bones. With the current project we explore the therapeutic potential of NPP1 inhibitors in mouse models for hypophosphatasia and chondrocalcinosis, using small-molecule inhibitors and inhibitory antibodies. Our specific research goals are (1) to optimize recently identified small-molecule inhibitors of NPP1 and to generate inhibitory monoclonal NPP1 antibodies, (2) to co-crystallize NPP1 with a small-molecule inhibitor and determine its detailed 3D-structure, (3) to generate a transgenic mouse that overexpresses NPP1 in postnatal articular cartilage, as a potential model for chondrocalcinosis, and (4) to test selected NPP1 inhibitors in cell-based calcification assays and in mouse models for hypophosphatasia and chondrocalsinosis." "Impact of the nutritional status on metabolic dysregulation during critical illness" "Lies Langouche" "Laboratory of Intensive Care Medicine" "Critically ill patients treated in the intensive care unit often develop a pronounced nutritional deficit because of the inability to feed orally and because nutrition administered via nasogastric tubes is poorly tolerated. Withholding parenteral nutrition was previously shown to enhance recovery and reduce infections in critically ill patients, as compared to early supplementing insufficient enteral feeding with parenteral nutrition. These beneficial effects of low caloric intake are partly related to the induction of a fasting response, which powerfully activates cell-protective and cellular repair pathways, promoting resilience to cellular stress. An important fasting-induced pathway is the switch from carbohydrate to lipid metabolism, with activation of hepatic ketogenesis. The fasting induced ketogenesis statistically mediated an important part of the outcome benefit of withholding parenteral nutrition in children, but not in adults, as in the latter the ketogenic fasting response was much smaller and appeared strongly suppressed by other illness-related factors. We postulate that in the context of critical illness related cellular and mitochondrial dysfunction, the beneficial switch from carbohydrate to lipid metabolism in low caloric conditions is hampered by PPARα suppression and a relative carnitine and choline deficiency. We hypothesize that activation of ketogenic pathways by a pharmacological PPARα modulator together with carbohydrate-low nutrition will increase ketogenesis and improve muscle integrity and function. We further postulate that refeeding hypophosphatemia reflects relative carnitine deficiency and lipid/energy provision exceeding the suppressed mitochondrial oxidative capacity in early sepsis or shock. As such an increased acylCarnitine/FreeCarnitine or a decrease in serum phosphate levels could be potential metabolic biomarkers of “not ready to feed” in ICU patients. Our hypotheses will be tested in a validated mouse model of cecal-ligation and puncture induced, antibiotics-treated polymicrobial abdominal sepsis by means of pharmacological treatments, and in 3 human studies."