Matthias Moor

Background: Chronic kidney disease (CKD) is a frequent cause of cardiovascular morbidity and mortality. CKD-associated mineral and bone disease (CKD-MBD) is a hall-mark and common complication of CKD, with consequences such as fractures and phosphate toxicity causing vascular calcification that drives early cardiovascular events. The failure of the kidney to sufficiently excrete phosphate in CKD-MBD arises in part due to end-organ resistance of the diseased kidney to the bone hormone fibroblast growth factor (FGF) 23. FGF23 is a strongly suspected pathogenic agent in CKD: Circulating FGF23 concentrations can be 1000-fold elevated in CKD, causing aberrant signaling resulting in inflammation and kidney fibrosis. In healthy kidney, FGF23 signals through an FGF receptor (FGFR) together with a co-receptor, Klotho, in the renal tubule and promotes mitogen-activated protein kinase (MAPK) signaling resulting in renal phosphate excretion. However, a better understanding of the kinases mediating FGF23-driven protein phosphorylation in the kidney is required for identification of potential therapeutic targets to prevent further kidney fibrosis and CKD progression during states of elevated FGF23 concentrations. Bone cells secrete FGF23 upon stimuli such as vitamin D, parathyroid hormone (PTH), inflammation, and phosphate. Phosphate itself is can generally be sensed by molecules including the sodium-phosphate cotransporter PiT-2 and FGFR. The Xenotropic and Polytropic retrovirus Receptor (XPR) 1 is part of a multi-protein phosphate sensor that includes phosphate transporter PiT-2. My preliminary data imply that XPR1 is important for osteoblast function and required for phosphate-driven FGF23 secretion by bone. Therefore, I hypothesize that XPR1 and its phosphate-sensing domain play a role in osteoblast endocrine function. Further, I hypothesize that some protein kinases responsible for phosphorylation events induced by FGF23 in the kidney in mice are also involved in FGF23 signaling in human kidney tissue. This project aims to advance the understanding of the molecules involved in the phosphate sensor-dependent secretion of FGF23 from the bone and renal FGF23 signaling in mice and humans. This work is split in 2 work packages (WP): WP 1: What is the role of the phosphate-sensing molecule XPR1 in FGF23 secretion? I aim to explore mechanisms of XPR1-mediated phosphate-driven FGF23 secretion. To pursue this work, I will employ conditional osteoblast-specific XPR1 KO mice and inducible XPR1 deletion in cultured osteoblast primary cells and cell lines. WP 2: What are the molecular contributors to FGF23 signaling in human kidney? Building on a preliminary phosphoproteomics screen, I will characterize 4 identified kinases involved in FGF23 signaling using precision-cut kidney slices from human kidney tissue from nephrectomies and test the consequences of kinase inhibition on the FGF23 signalosome. Significance: A better insight in phosphate sensing and FGF23 secretion by the bone and the FGF23-driven protein phosphorylation networks could help to identify novel therapeutic targets for patients with CKD-MBD, ultimately paving the way for therapeutic strategies to complement the currently available phosphorus-limiting therapies and for helping to diminish the burden of vascular morbidity in CKD.