INNOVATION FUND Technology and AI in Healthcare SHOWCASE 2019 View Innovation Fund Showcase 2019 Awardees View Photos from the Event INNOVATION FUND Technology and AI in Healthcare SHOWCASE 2019 View Innovation Fund Showcase 2019 Awardees View Photos from the Event

Gregory M.T. Hare

As an Anesthesiologist and Clinician Scientist at St. Michael’s Hospital, University of Toronto, my research has focused on characterizing the hypoxic cellular responses to acute anemia; vital for assessment of the impact of acute anemia on tissue oxygen homeostasis and efficacy of treatment modalities including treatment of anemia, RBC transfusion and development of novel blood substitutes including hemoglobin based oxygen carriers (HBOC). The clinical focus of this research is to develop treatment strategies that reduce the risk of organ injury and mortality associated with acute and chronic anemia.

In our translational models of acute anemia, we have observed that the adaptive cardiovascular responses to acute and chronic anemia are critical to maintaining adequate tissue oxygen delivery to vital organs including the brain, heart and kidneys. In addition, adaptive cellular responses include increased expression of two important hypoxic molecules, hypoxia inducible factor -1α (HIF-α) and neuronal nitric oxide synthase (nNOS). Our data supports the hypothesis that the increase in nNOS is protective during anemia, and that nNOS deficient mice are specifically susceptible to anemia induced mortality. Pursuit of the cellular mechanism has led to the finding that nNOS-derived NO strongly influences the expression of HIF-1α in tissue of anemic mice, in response to subtle changes in tissue PO2. In the cerebral cortex of anemic mice, HIF-1α expression is dependent on nNOS.  The mechanism involves S-nitrosylation of pVHL thereby inhibiting HIF-α degradation. We have extended these findings to a HIF (ODD) luciferase mouse model and have demonstrated real-time stabilization of HIF in brain, kidney and liver of anemic mice.  Utilizing this model, we have defined organ-specific hemoglobin thresholds for HIF stabilization during anemia by demonstrating that: basal HIFα levels in the brain contribute to maintaining oxygen homeostasis; and that HIF-1α and HIF-2α are differentially regulated within the brain, liver and kidney during anemia. In addition, the dependence of HIF expression on nNOS is specific to anemia and is not observed during exposure to atmospheric hypoxia. These fundamental findings provide a foundation for: 1) understanding the mechanisms of anemia induced mortality and brain injury; 2) identifying clinically relevant biomarkers (HIF-erythropoietin) to develop treatments to reduce anemia related morbidity and mortality; and 3) the potential prevention and reversal of anemia related morbidity and mortality by a number of treatment modalities including; iron and erythroid stimulating agents, appropriate RBC transfusion and novel oxygen therapeutics including HBOCs.

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