Graduate Studies Faculty

Preceptor Rotations

Faculty Mentorship

Profile

The Zundel Lab studies the mechanism & consequences of acute hypoxia (periods of hypoxia/ischemia (H/I) of variable duration occurring frequently during tumor growth) in cancer progression. Tumoral H/I is a physiologic stress that increases the rate of both gene mutation & genomic instability. This, in turn, leads to the selection of oncogenic gain-of-function & the loss of tumor suppressors, providing the expanding tumor with the ability to adapt to the harsh microenvironment while also leading to increased tumorigenic capacity. Following extended adaptation to acute hypoxia, the resulting tumor is more aggressive, invasive & metastatic as well as radiation & chemo-resistant than less ischemic tumors. 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 acute hypoxia & how these processes go awry during cancer progression is to identify essential pathway nodes within H/I regulatory pathways that cannot be by-passed on parallel paths & therapeutically target these nodes 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. Further, as O₂-mediated responses are defined in normal tissues, pathophysiologies having causal H/I-regulated components (such as  pulmonary disorders (i.e. COPD), cardiac and vascular disorders (i.e. myocardial infarction & stroke), diabetes, infection, obesity, , etc) could be similarly defined & therapeutically targeted using a similar approach as that used for cancer.