Carbon Monoxide Inhibition of Mitochondrial Function and Efficacy of a Novel Antidotal Therapeutic for Carbon Monoxide Poisoning

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

? DESCRIPTION (provided by applicant): Carbon monoxide (CO) exposure is the leading cause of human poisoning in the United States, with 50,000 cases every year. Current therapy, normobaric or hyperbaric oxygen, has limited effectiveness and is difficult to deliver. There is currently no antidotal therapy. Our understanding of the toxic effects of CO is two-fold: CO directly binds to hemoglobin reducing oxygen carrying capacity of the blood, and CO directly binds to a heme in cytochrome c oxidase, inhibiting mitochondrial respiration. The major sequelae of CO poisoning - cardiovascular dysfunction and acute and long term neurologic deficits - are dependent on impaired mitochondrial function. Our lab has developed an agent, recombinant human neuroglobin (rNgb), with a very high affinity for CO, which has the potential to reduce the toxic effects of CO poisoning. We, therefore, propose the hypothesis that treatment with rNgb reverses the toxic effects of CO poisoning on mitochondrial function. To test the hypothesis, we will first conduct in vitro studies using a Clark-like electrode to further characterize the toxic effects of CO on isolated mitochondria and heart tissue respiration and demonstrate that rNgb can reverse the toxic effects of CO on mitochondrial respiration. Second, in an in vivo CO poisoning model, we will show that treatment with rNgb can reverse pathologic changes as assessed by functional MRI changes (fractional anisotropy) and blood levels of lactate and glucose. These results will provide pre-clinical proof of concept for rNgb to act as a potential therapeutic agent in CO poisoning. In parallel, through the NIH SMARTT program we are conducting pharmacology and toxicology testing and scaling up drug manufacturing capabilities. The NRSA award will allow me, a pulmonary and critical care trained fellow, a unique opportunity to leverage the existing research and development infrastructure of my mentor, Dr. Mark Gladwin, to gain advanced training in animal models of disease, mitochondrial biology, and pathophysiologic outcomes. In addition, I am pursuing an MBA in the entrepreneurial track at the Tepper School of Business at Carnegie Mellon University, which will provide extensive training in finance, statistical modeling, and critical tools for bringing a potential therapeutic drug from bench to bedside. The resources and experience of my mentor Dr Gladwin, an expert in NO and globin biochemistry, as well as the translational development of drugs from the laboratory to the clinic, and my co- mentor Dr Shiva, an expert in mitochondrial biology, combined with the expansive array of resources available at the University of Pittsburgh, will allow me develop new translational research skills with a specific focus on development of novel therapeutic strategies.