Katherine Wood, PhD

Research Focus

Dr. Wood’s research centers on molecular and cellular mechanisms of dysfunctional redox-dependent homeostasis in vasculo-, neuro- and hemato-symptomatic disease states, such as anemia, ischemic stroke and sickle cell disease (SCD). High levels of oxidative stress that uncouples the nitric oxide-soluble guanylate cyclase-protein kinase G (NO-sGC-PKG) signaling pathway for vascular relaxation responses to altered blood flow are common to these disease states.  Cytochrome b5 reductase 3 (CYB5R3), also known as methemoglobin reductase, is critical for maintaining the sensitivity and signaling integrity of the NO-cGMP-PKG pathway.  CYB5R3 is important for recycling oxidized sGC heme iron (Fe³⁺) back to its NO-receptive Fe²⁺ state, which has been shown both in vitro and in mouse models of NO resistance, pulmonary hypertension, brain infarct and anemia.  

Molecular and Cellular Studies of CYB5R3-NO-sGC-PKG Signaling in Disease

It is noteworthy that some disease states occur with greater frequency and worse outcomes in persons of African ancestry: SCD, ischemic stroke, anemia. The reasons for this, however, remain largely unknown. There are more than 40 identified variants of CYB5R3 and a variant of particular interest is CYB5R3 T117S because it occurs with high frequency (0.23 minor allele) in persons of African ancestry but is rare in other racial groups (<1%).  The T117S variant has roughly 50% decreased reductase activity, rendering it a logical mediator of impaired NO-cGMP-PKG signaling in these disease states. A novel mouse model of T117S is being used to investigate the variant’s effects on ischemic stroke, as well as SCD vasculopathy and anemia.  Parallel studies with CYB5R3 knockout or overexpression in specific cell types (smooth muscle cell, endothelial cell, platelet, and bone marrow) are also ongoing to understand the importance of CYB5R3 activity at a cell-specific level.  

Translational Research
 
The goal of these studies is to uncover identifiers/determinants of disease processes that can be used at the clinical level to improve diagnoses and treatment options for high-risk patients.  Opportunities for harnessing the potential of CYB5R3-targeted pharmaceuticals, such as sGC agonists (stimulators and activators), for improved clinical management of lung, blood and vascular diseases in high-risk patients are also being explored and exploited by Dr. Wood.