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Overview: The Zundel Lab studies the mechanism & consequences of acute hypoxia (periods of hypoxia/reperfusion of variable duration occurring frequently during tumor growth) in cancer progression. To comprehensively understand how normal tissues respond to hypoxia/ischemia & how these processes & functions are altered or co-opted during tumorigenesis, we use a combination of functional genetics, genomics, HT-Y2H, proteomics & bioinformatics to examine both the normal & oncogenic molecular architecture underlying oxygen-sensing and response mechanisms. Such a systemic approach is serendipitously uncovering novel aspects of basic cellular functions, such as energy metabolism, novel consequences of O2-related protein post-translational processes (Pro, His, Arg-hydroxylation, neddylation, ubiquitylation & proteolysis), translational arrest, IRES-mediated translational initiation, mRNA stability, & stem cell biology to name but a few. Our goal in comprehensively defining the molecular responses to hypoxia & how these processes go awry during cancer progression is to identify essential pathway nodes that cannot be by-passed & therapeutically target these nodes & regulatory pathways with high specificity. We feel that this approach will ultimately lead to the development of novel therapies as well as the identification of stage-specific diagnostic and prognostic markers. We also feel that as we define O2-mediated responses in normal tissues, other hypoxic/ischemic pathophysiologies such as pulmonary disorders (i.e. COPD), cardiac and vascular disorders (i.e. myocardial infarction & stroke), diabetes, infection, obesity, other certain aging-related disorders, etc. could be similarly defined & therapeutically targeted.