Key enzyme regulators of the hypoxia response and collagen synthesis as therapeutic targets

Maintenance of oxygen and extracellular matrix (ECM) homeostases is crucial for normal development and physiology, and several pathologies are associated with hypoxia or ECM abnormalities. We focus on the central enzymes regulating these two fundamental biological processes: 1) the prolyl 4-hydroxylases (P4Hs) that control the hypoxia response pathway via determination of the oxygen-dependent fate of the hypoxia-inducible transcription factor HIF, and 2) the key enzymes of collagen synthesis, the collagen P4Hs, lysyl hydroxylases (LHs) and lysyl oxidase (LOX). My group has extensive experience in studying the mechanisms and functions of these enzymes. We e.g. made the pioneering experiments towards development of HIF-P4H inhibitors by being the first to produce recombinant human HIF-P4Hs and to determine their catalytic and inhibitory properties in detail. The first HIF-P4H inhibitor, developed by our long-term collaborator FibroGen, has recently been approved for treatment of anemia of chronic kidney disease. The aims of the current project are centered on two main questions: 1) Does inactivation of selected HIF-P4Hs, C-P4Hs, LHs or LOX have protective or adverse effects in inflammation, fibrosis and cancer, and 2) is prolyl hydroxylation a post-translational modification that occurs beyond HIF and collagens and what is the physiological relevance?