Hypoxia Research

The cellular adaptation to an oxygen deficiency takes place by stabilizing and activating the transcription factor hypoxia-inducible factor (HIF). The prolyl-4-hydroxylase (PHD) enzymes hydroxylate the α-subunit of HIF on two critical prolines (P402 and P564). This reaction is directly dependent on the oxygen substrate concentration. HIF hydroxylation results in pVHL-dependent ubiquitination and rapid degradation of the HIF-1α protein. Under hypoxic conditions, hydroxylation is prevented due to the lack of substrate, HIF-1α remains stable, can heterodimerize with the HIF-1β subunit and initiate oxygen-dependent gene expression after nuclear translocation and recruitment of co-factors.

Functionally, HIF target genes influence cell physiological functions such as erythropoiesis, glycolysis, angiogenesis etc. in order to maintain cell homeostasis under the hypoxic conditions. The PHD enzymes are potential candidate molecules for modulating cellular adaptation to hypoxia. A goal is therefore to further elucidate their organ and isoform-specific function, use of co-factors and the consequences of their inhibition.

Actin is one of the most highly preserved eukaryotic proteins and a central component of the cytoskeleton. It is involved in a variety of cell functions, including cell cytokinesis, membrane dynamics, and cell motility. In addition, the dynamic modulation of the actin cytoskeleton, for example via the transcription factor "Serum Response Factor (SRF)" and its co-factor MRTF ("Myocardin-Related Transcription Factor"), provides signals for changing gene expression. Hypoxic conditions influence actin dynamics and all processes dependent on them, whereby the signaling pathways involved are complex and so far only partially known. A better understanding of the hypoxia-related changes in cytoskeletal regulation could therefore lead to a better understanding of many pathological processes, e.g. Cell migration and fibrosis formation in the ischemic tissue.

Heart failure is one of the most common causes of morbidity and mortality worldwide. At the cell level, the injured heart reacts with complex and stereotypical remodeling processes in cardiomyocytes and in the so-called non-cardiomyocytes (fibroblasts, endothelial cells, immune cells, etc.). Striking changes in these cells are redox-dependent modifications to regulatory proteins. An imbalance in the production of reactive oxygen species and an altered "redox state" is involved in many cardiac stress reactions that are involved in the development of heart failure. As part of our projects, we develop technical tools for the quantification of redox changes in cardiomyocytes and non-cardiomyocytes and their consequences for the function at cell and organ level.