Description of Research
My research efforts have focused on understanding the cellular and molecular mechanisms underlying the response of normal tissues and tumors to hypoxia (low oxygen tensions). Hypoxia is the primary physiological stimulus controlling erythropoiesis and red blood cell production. Dysregulated erythropoiesis clinically manifests in the development of anemia or polycythemia. My research has focused on elucidating the cellular and molecular mechanisms by which the PHD/VHL/HIF signaling pathway regulates erythropoiesis for the treatment of red blood cell disorders. To this end, we have identified osteoblasts in the bone marrow microenvironment as an endogenous source of EPO that can be activated by PHD inhibition for the treatment of anemia. Current studies are focused on expanding these studies to determine how VHL/HIF signaling in the bone marrow microenvironment controls erythropoiesis.
In addition to its physiological role in the regulation of erythropoiesis, hypoxia and the downstream VHL/HIF signaling pathway plays an important role in tumor initiation, progression and therapy resistance. My research investigates the molecular mechanisms by which dysregulation of VHL/HIF promotes tumor growth, survival and metastasis with the goal of identifying and developing novel therapeutic strategies for the treatment of advanced metastatic disease. To this end, we have developed targeted therapeutics to treat metastatic disease by targeting novel HIF targets such as the receptor tyrosine kinase AXL. I have extensive experience investigating mechanisms by which hypoxia and VHL/HIF signaling pathway promotes tumor progression and metastasis in kidney, ovarian and breast cancer using mouse models, biochemical and molecular biological approaches. Current studies are aimed at identifying additional therapeutic targets driven by PHD/VHL/HIF signaling in the tumor microenvironment as well as evaluating the therapeutic value of targeting these pathways for cancer therapy.