Protective Effects of CO
Our work stems from the study of heme oxygenase-1 (HO-1), which has been labeled a protective gene. HO-1 generates CO endogenously as it catabolizes heme.
More recently, we have expanded our studies to include biliverdin (BV) and more specifically biliverdin reductase (BVR) that converts BV to bilirubin (BR). BV has been shown to exert potent protective effects in a number of in vitro and in vivo models with the assumption that it is the powerful anti-oxidant effects that underlie the mechanism of action.
To address certain questions, we have generated conditional knockout mice for HO-1 and BVR allowing us to delete either gene in a tissue-specific manner.
More recently we discovered that BVR colocalizes with Toll-like receptor-4 (TLR4) and regulates the response of the cell to bacterial endotoxin. Functionally, this interaction prevents the upregulation of pro-inflammatory cytokines and improves survival in a model of acute hepatitis in mice.
We furthered these findings in a paper published in PNAS in 2011 where we demonstrate that BVR becomes nitrosylated and, as such, translocates to the nucleus where it binds to the TLR4 promoter to block expression.
We conclude that BVR is an innate regulator of the inflammatory response. Studies are now underway using the BVR conditional knockdown in macrophages in acute liver injury and regeneration. Biliverdin is now under pre-clinical evaluation for treatment of inflammatory disorders with a new biotech company Viridis Biotech for leading the development.
We also maintain a very active bacterial sepsis program, where we have shown that inhaled CO can protect mice from acute severe bacterial sepsis and shock. One mechanism by which CO provides protection is via enhanced activation of the inflammasome. This is evidenced by augmented caspase-1 activation and IL-1Bexpression as well as bacterial clearance in the peritoneum.
Of note is that CO targets the bacterium versus the macrophage, acting to drive ATP release from the bacteria that in turn activates the macrophage. We conclude that CO acts to sense the environment for the presence of bacteria. The binding of endotoxin to TLR receptors activates HO-1 as signal 1. The CO generated then diffuses into the
environment and if a bacteria is present, ATP will be generated that acts as signal 2 binding to the P2X7 receptor and fully activating the macrophage to kill. Such a model, much like T-cell activation, permits a elegant system of innate inflammatory regulation, preventing unnecessary cell activation.
We continue our work in models of vascular injury related to arteriosclerosis, which leads to chronic rejection, as well as vascular trauma. We have elucidated that CO augments vascular repair via select targeting of calcium channels which lead subsequently to downstream activation of Akt and NO generation via eNOS. Further that CO enhances recruitment of endothelial progenitor cells to repair the injured vessel in mice. Inhaled CO is currently in clinical trials to improve kidney function after transplantation. Data generated in a large animal model was the proof-of concept study that led to the clinical trial.
Cancer and Metabolism
Our team is employing a multidisciplinary approach to incorporate the critical and challenging clinical questions regarding lung, prostate, and gastric cancers that can then be brought into the laboratory for identification of novel biomarkers, metabolic signatures, and preclinical animal models of cancer. This research is supported with ARC funding.
Importantly, we will explore small molecule drug design directed toward innovative therapies. Our goal is to merge clinical and basic research expertise to enable competitive program grant applications, creation of intellectual property, and investigational new drugs for cancer treatment.