ECM and Hypoxia

Compartmentalization of growth factor signaling in vascular endothelial cells

The growth of blood vessels is an essential biological process during embryonic development. On the other hand, aberrant growth and altered functions of the vasculature are involved in many common diseases. The extracellular matrix (ECM) surrounding the vessels and accompanying stromal cells have important roles providing the structural support and supplying factors that regulate endothelial cell functions. In this project we are interested in signaling pathways that regulate the synthesis and modifications of perivascular ECM constituents and the feedback loops between the ECM, stromal cells and endothelial cells, and how their dysfunctional interactions can lead to vascular diseases. To accomplish our aims we use biochemical, cell biological and tissue culturing models, advanced microscopic imaging and image analysis, as well as genome and system wide mRNA and protein profiling techniques. Cell culture experiments are accompanied by mouse models, and analyses of tissue samples from vascular anomalies.

2-Oxoglutarate-Dependent Enzymes as Novel Therapeutic Targets in Diseases

2-oxoglutarate-dependent dioxygenases (2OGDDs) are an enzyme family of ~60 members in human that share the same reaction mechanism but act on different substrate varying from proteins to DNA, RNA and fatty acids. 2OGDDs require as cofactors Fe2+, 2-oxoglutarate and O2. 2OGDDs include the collagen prolyl 4-hydroxylases, the hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs /PHDs / EglNs), transmembrane P4H and the hypoxia-inducible factor asparaginyl hydroxylase FIH. Many 2OGDDs act on chormatin structure as erasors, such as the DNA demethylating TETs and numerous histone lysine demethylases. 2OGDDs can be targeted with small molecule compounds, such as the HIF-P4H inhibitors that have been accepted for the treatment of anemia. We hypothesize that these inhibitors can also be used to treat ischemic, metabolic and inflammatory conditions. We also anticipate that other 2OGDDs can be targeted with small molecule inhibitors to for example to treat cancer.

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Intracellular redox compartments in Hypoxia-signalling and associated diseases

A limited supply of oxygen (hypoxia) has profound effects on both cellular and whole body function and contributes to the pathogenesis of diabetes mellitus, atherosclerosis, thrombosis, pulmonary hypertension and tumorigenesis. The hypoxia-inducible factor-1alpha(HIF-1alpha) plays a key role in the response to hypoxia. In addition to hypoxia, HIF-1alpha also responds to growth and coagulation factors and hormones by using reactive oxygen species (ROS) generated by various enzymes in different cellular compartments. Therefore, it is the overall aim of the project to understand the mechanistic link between hormone-regulated metabolism, compartment-specific changes of ROS and modulation of HIF-1alpha expression and degradation in vivo and in vitro.

Key enzymes in the synthesis of collagens and the response of cells to hypoxia

Collagen prolyl 4-hydroxylases (C-P4Hs), lysyl hydroxylases (LHs) and lysyl oxidases (LOs) have essential roles in collagen synthesis. A further P4H family (HIF-P4Hs) and an asparaginyl hydroxylase (FIH) regulate the stability and activity of the hypoxia-inducible transcription factors (HIFs), αβ dimers, that play a central role in oxygen homeostasis. To understand the functions of these enzymes, their roles in development and various pathological conditions, and their potential as therapeutic targets, we are utilizing a wide repertoire of methods ranging from analysis of the catalytic and inhibitory properties of the recombinant enzymes to cell biology and animal models. Interestingly, the key enzymes of collagen synthesis are HIF targets and thus regulation of extracellular matrix homeostasis and the hypoxia response are closely linked. Detailed information on the key regulatory enzymes of the hypoxia response will have a major impact in furthering our understanding of how cells and tissues survive and respond to situations of acute or chronic hypoxia. Such information will create novel opportunities for pharmacological intervention in pathological conditions characterized by insufficient oxygen levels such as anemia and ischemia. We are collaborating with FibroGen Inc. in this aspect.

Conserved Collagens in Cell–Matrix Homeostasis

Besides conferring shape and stability to tissues, the extracellular matrix (ECM) plays a crucial role in controlling cell differentiation and function, and it is associated with a wide spectrum of common diseases including arthritis, atherosclerosis, cancer, fibrosis, skeletal deformity and poor wound healing. The collagen family of proteins plays a dominant role in maintaining the integrity of tissues. Twenty-nine types of collagen have been found in vertebrates, and we address the physiological and pathological significance of two evolutionarily conserved subgroups of collagens, the ubiquitously occurring basement membrane (BM)-associated collagens XV and XVIII, also called the multiplexin subgroup of collagens, and the structurally homologous transmembrane collagens XIII, XXIII and XXV. These collagens perform not only structural functions but also have important regulatory roles in the pericellular environment in supporting cell growth and differentiation.

We focus on the development of new algorithms for studying molecular networks in cancer, perform integrative analyses of the tumor microenvironment, with particular emphasis on the role of the extracellular matrix and we provide bioinformatics and data analysis as a service to our collaborators & partners.