Ben Wielockx

The role of HIF prolyl hydroxylases (PHDs) in inflammation and tumor angiogenesis

Previous and current research

All organs in our body depend on the sufficient amount of oxygen to survive. That’s why the maintenance of oxygen homeostasis at the cellular level is very important and has been the topic of many studies for the past decade. In addition, an inadequate oxygen supply, also called hypoxia, is a prominent feature in various inflamed and/or diseased tissues, including rapidly growing tumors, healing wounds and sites of bacterial infection.

The central mediator during hypoxia is the transcription factor HIF (hypoxia inducible factor) whose function is to directly regulate genes involved in fundamental processes like growth, death and survival. Recently, it was demonstrated that this process is strictly regulated at the post-translational level by a class of oxygen sensitive enzymes, called HIF-prolyl hydroxylases (PHDs) that initiate the breakdown of HIF by hydroxylating it. To date little is known about the exact function of these enzymes in vivo, and therefore our group is investigating their role during local inflammation and tumor development in mice, with a clear focus on the cross-talk between inflammatory cells and the surrounding tissue (e.g. skin or tumor).

Fig: Section of a mouse tumor stained for endothelial (red) and hypoxic cells (green)

Future projects and goals

We want to gain a better understanding of the interplay between the different cell types and their relation to oxygen homeostasis under physiological as well as pathological conditions in mice. In more detail, we will study the function of the PHDs using several established disease models (e.g. wound healing, local infection, chemically/genetically induced tumor development) in inbred, conditional deficient or transgenic mice.

About

2002: PhD in Biotechnology, Ghent University, Belgium 2002-2004: Postdoc at the DMBR-VIB, Ghent, Belgium 2004-2007: Postdoc in the ECBP group - Inst. of Pathology - TUD. since 2007: Emmy Noether group leader (DFG) – Inst. of Pathology – TU Dresden

Selected publications

Klotzsche-von Ameln, A., Muschter, A., Mamlouk, S., Kalucka, J., Prade, I., Franke, K., Rezaei, M., Poitz, D.M., Breier, G., and Wielockx, B. (2011): Inhibition of HIF Prolyl Hydroxylase-2 Blocks Tumor Growth in Mice through the Anti-Proliferative Activity of TGFb, Cancer Res, 71(9):3306-16

Wielockx, B., Staelens, J., Puimège, L., Van Roy, F. and Libert, C. (2007):  Description and chromosomal mapping of the resistance against tumor necrosis factor–induced lethal shock of DBA/2 mice. J. Immunol. 178(8):5069-75

Wullaert, A*., Wielockx, B.*, Van Huffel, S., Bogaert, V., De Geest, B., Papeleu, P., El Bakkouri, K., Heyninck, K., Libert, C., and Beyaert R. (2005) : Adenoviral gene transfer of ABIN-1 protects mice from TNF/Galactosamine-induced acute liver failure and lethality, Hepatology; 42(2), 381-9, (*equally contributed).

Van Molle, W., Wielockx, B., Mahieu, T., Takada, M., Tanigushi, T., Sekikawa, and Libert, C.(2002): Heat shock protects against TNF-induced lethal inflammatory shock by induction of HSP70: lessons from hsp70 knockout mice and implications for TNF-based antitumor treatment, Immunity, 16, 685-695

Wielockx, B., Lannoy, K.,Shapiro, S. D.,Vandekerckhove, J., and Libert, C (2001): Inhibition of Matrix Metalloproteinases blocks TNF-induced Lethal Hepatitis and apoptosis, Nat. Med. 7, 1202-1208

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