Research Description

My current area of active investigation is related to the structure-function relationships and physiological role of the protein, peroxiredoxin 6. The peroxiredoxins are a recently described family of antioxidant enzymes that for the most part function as thioredoxin peroxidases. But, peroxiredoxin 6 is unique as a bifunctional enzyme with both glutathione peroxidase and phospholipase A2 (as well as acyl transferase) activities. Of importance, the enzyme can directly reduce phospholipid hydroperoxides thereby serving to repair the peroxidized cell membranes that are associated with oxidant stress. We have investigated the special features of the protein that permit phospholipid binding and subsequent hydrolysis or reduction of the bound substrate. We have shown that peroxiredoxin 6 through its peroxidase activity serves as a major anti-oxidant enzyme in the lung and also through its phospholipase A2 (PLA2) activity participates in the normal turnover of phospholipids. We have recently shown that the PLA2 activity through generation of signaling products is required for the activation of NADPH oxidase in phagocytic cells, endothelium, and other cells. We also have demonstrated that surfactant protein A (SP-A) inhibits the PLA2 activity of Prdx6 and thereby inhibits NOX2 activation. We further showed that a 9 amino acid peptide derived from SP-A is the inhibitory sequence responsible for the NOX2 inhibition. Since NOX2 is a major source of oxygen-derived radicals,  the use of this peptide to inhibit NOX2 activation could be a useful therapeutic and, indeed, we have shown marked protection against the lung injury associated with the syndromes of both Acute Lung Injury and Sepsis in experimental mouse models. We are currently pursuing these findings in a large animal model more closely related to human physiology. Thus, understanding the role of peroxiredoxin 6 in cell physiology has led to studies with a specific inhibitor of its phospholipase A2 activity with the potential to treat a variety of human diseases    associated with lung inflammation and oxidative stress.