My laboratory has a longstanding interest in G-protein coupled receptors and how they regulate both airway and vascular smooth muscle tone. The primary focus is devoted to signaling by adrenergic and prostanoid receptors. A major focus at this time is investigation of oxidative stress as an inflammatory mechanism that attenuates the response to b-agonists during more severe asthma exacerbations. Oxidative stress results from the activity of peroxidase enzymes such as eosinophil peroxidase (EPO) and myeloperoxidase (MPO) that are released by infiltrating eosinophils and neutrophils in the asthmatic airway. Preliminary work has shown that both the b-agonist and b2-adrenergic receptor are structurally susceptible to oxidative modification (e.g., nitration) that limits their activity. Nitration of the agonist decreases its ability to bind the receptor, whereas nitration of the receptor decreases its ability to activate its associated G-protein. The laboratory makes use of a variety of molecular, cell singaling, and physiological techniques that include both cell-based and animal models. Areas of active investigation include:
- Identify the types of oxidative modifications that decrease agonist and receptor function (nitration, bromination, chlorination, etc.). Peroxidases differ in their substrate specificity, reactive specifies generated, and susceptibility to inhibition, so these results will inform which peroxidase inhibitors may be more effective as a rescue strategy. This work will be carried out in cell-based models.
- Identify the amino acid residues in the receptor that are oxidatively modified. This will be a combination of cell-based and chemical methods (mass-spectroscopy). Results of these studies may inform the development of allosteric modulators that can prevent nitration and rescue receptor function.
- Determine whether the receptor is directly oxidized by peroxidases (i.e., is the receptor an enzyme substrate) vs indirectly by enzyme-generated reactive species such as nitrite or peroxynitrite. This is predominantly cell-based work that will provide information to select peroxidase inhibitors vs antioxidants for potential rescue agents.
- Determine whether peroxidase inhibitors and antioxidants can rescue b-agonist signaling, smooth muscle relaxation, and bronchodilation. This work will be carried out in both cells and animals to (i) provide proof-in-principle of peroxidase inhibitors and/or antioxidants as rescue agents, and (ii) provide the supporting basis for future clinical trials.
A second area of focus in partnership with the rare lung disease group is the investigation of eIF2a kinase (aka GCN2) deficiency as model for pulmonary capillary hemangiomatosis, PVOD and/or PAH. Mice lacking the eIF2a kinase gene have been subjected to chronic hypoxia to model PAH and cyclophosphamide to model chemotherapy-induced PVOD. This work is in its infancy; preliminary studies in animal models are ongoing and results are pending.
I am also the director of a service center that provides bronchoscopies for research purposes.