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Gene-targeting of oxygen sensors to study the molecular mechanisms of hypoxia signaling in vivo.

Objective

Low oxygen supply to tissues (Hypoxia) plays an important role in the pathophysiology of ischemic cardiovascular disease, cancer and chronic lung disease, which are the most common causes of mortality. Cells induce under this unfavorable oxygen conditions an adaptative gene expression programme mediated by the hypoxia-inducible transcription factor HIF- 1. This gene expression programme contributes to the pathogenesis of cancer and hypoxic pulmonary hypertension will protecting against the ischemia and infarction. The project will centre on the in vivo relevance of a novel family of prolyl-hydroxylases (PHDs) that has been recently revealed as mammalian oxygen sensors involved in the regulation of HIF-1. Due to the recent discover of these molecules, the understanding of the relative in vivo contribution of each of PHD isoforms in pathogenesis induced by hypoxia. To answer these major questions there will be used knock out and transgenic animal models available in the host laboratory. On the other hand, since neural cells are extremely sensitive to hypoxic conditions during cerebral strokes there will be analyze the biological relevance of these PHD in neuronal cells by using in vivo tissue-specific specific modification of each PHD isoform activity. In addition, HIF-VEGF pathway is essential for tumor progression. We also dissect the contribution of each PHD isoform in tumor growth and whether the effect of inhibition of PHD in cancer. The delineation of the PHD-HIF-1 pathway has now provided multiple targets and will hopefully lead to the discovery of pharmacologic agents that can be use for Proof-of -principle experiments in animal models and as a lead for the development of agents that can be used in clinical trials To this date, my PhD training and my post-doctoral career bas been focused on cellular response to hypoxia and in particular on HIF transcription factors. I have been working in the intracellular signalling mechanisms that connect oxygen sensing and activation of HIF transcription factors. My work has involved complex transcriptional analysis, protein-DNA binding assays as well as lipid biochemistry analysis since we found evidence for the involvement of lipid-dependent signal transduction in the regulation of these transcription factors. All these studies have been done using cell culture models. The use of animal models that has been absents from my research career will further my knowledge in this interesting scientific field. Due to the high degree of expertise cellular response to hypoxia and related fields and specialized animal models techniques available in Dr. Carmeliet's laboratory and my proven knowledge of cellular response to hypoxia, I feel that investigation of in vivo relevance of oxygen sensors will be valuable expansion of my research and will fulfill my desires to broaden my knowledge of novel experimental techniques and applications.

Funding Scheme

RGI - Research grants (individual fellowships)

Coordinator

FLANDERS INTERUNIVERSITY INSTITUTE FOR BIOTECHNOLOGY VZW
Address
49,Herestraat 49 Kul / Campus Gasthuisberg
3000 Louvain / Leuven
Belgium