Krick-Brooks Chair in Nephrology

Professor of Medicine

Education

MD - Johann Wolfgang Goethe University

Clinical Interest

Research Keywords
Molecular oxygen-sensing; the pVHL/HIF pathway; erythropoiesis; EPO; iron metabolism; glucose and fat metabolism; ischemic cell injury and regeneration; progression of chronic renal disease; von Hippel-Lindau disease (VHL); kidney cancer and renal cystogenesis; hepatic steatosis; conditional gene targeting technology and transgenesis; embryonic stem (ES) cells; mouse model systems.
Research Description

LABORATORY of OXYGEN METABOLISM The Haase research group has long-standing expertise in the molecular, genetic and metabolic analysis of mammalian hypoxia and hypoxia-inducible factor (HIF)-mediated responses, as well as HIF-related transcriptional biology. Hypoxia-Inducible Factors HIF-1 and HIF-2 are oxygen-sensitive basic helix-loop-helix transcription factors that regulate biological processes, which facilitate both oxygen delivery and cellular adaptation to oxygen deprivation. HIFs consist of an oxygen-sensitive alpha-subunit, HIF-alpha, and a constitutively expressed beta-subunit, HIF-beta, and regulate the expression of genes that are involved in energy metabolism, angiogenesis, erythropoiesis and iron metabolism, cell proliferation, apoptosis and other biological processes. HIF activity is controlled by prolyl-4-hydroxylase domain (PHD) enzymes, which function as oxygen sensors that target the a-subunit of HIF for hydroxylation and subsequent proteasomal degradation via the von Hippel-Lindau (VHL)-E3 ubiquitin ligase. These enzymes represent excellent drug targets and several compounds are currently in clinical trials for the treatment of renal anemia (Koury and Haase, Nat Rev Nephrol, 2015). Initially, the Haase research program started with the generation of the first mouse model for VHL disease, which reproduces clinical manifestations of the disease, such as renal cysts, hemangiomas and polycythemia. As part of this effort, the laboratory has established specific roles for HIF-1 and HIF-2 in the pathogenesis of VHL-associated liver hemangiomas, in the hypoxic induction of hepatic and renal erythropoietin and in the regulation of glucose and fatty acid metabolism. A main focus of the laboratory is on understanding the molecular and cellular basis of hypoxia responses in the adult kidney and in kidney development. As part of this effort the laboratory have spearheaded studies that established novel molecular links between hypoxia, HIF signaling and the progression of chronic kidney disease. The lab furthermore have spearheaded studies that aim at defining the interplay between alterations in energy metabolism, cellular differentiation and function, cell-cell interactions, inflammation and tissue repair mechanisms. For this the laboratory has developed novel technology that permits spatial high-resolution imaging of metabolites in tissue sections. Another major research focus is on the role of HIF in the regulation of EPO synthesis in kidney and liver as well as iron metabolism. The Haase laboratory has generated several genetic models of polycythemia and anemia and has contributed to defining HIF’s role in iron metabolism and to the development of drugs (HIF stabilizers) that are currently in clinical trial for the treatment of renal anemia. Specifically, the group has identified HIF-2 as the key regulator of renal EPO synthesis and established that HIF coordinates erythropoiesis with iron metabolism by directly regulating iron uptake and release.