My laboratory is interested in the oxidative stress response and the regulation of protective genes. One particular gene of interest is heme oxygnease-1 (hmox-1) which when induced, imparts potent protective effects in numerous models of inflammation. The hmox-1-/- mouse is 95% lethal with the 5% that survive to term dying early from a heightened inflammatory response and end organ damage. Humans deficient in hmox-1 show a similar phenotype as the mouse, suffering also from severe mental retardation. We speculate that a similar pathology exists in the mouse that leads to impaired cognitive behavior, but also an inability to defend against otherwise benign inflammatory stimuli such as bacteria and viruses. It has been well described that one of the products of hmox-1 activity, carbon monoxide (CO), is an important neurotransmitter, critically involved in memory and intracellular signaling in most if not all cell types and of particular importance in the brain and peripheral nervous system. Many of the aspects of hmox-1 in providing protection can indeed be attributed to the generation of CO. Exogenous CO administered at low concentrations can mimic that observed with hmox-1 and in many cases rescue the hmox-1-/- phenotype. The generation of the hmox-loxp mouse which is our goal, will be extremely important in improving our understanding of hmox-1 in development, injury and inflammation and as a signaling molecule in the brain and elsewhere and offer important and critical insight into the observed phenotype observed in the absence of functional hmox-1. Our focus of our work and the grant is that HO-1/CO modulate the inflammatory response and that this is related in part to CNS signaling via the vagus. In essence, HO-1/CO reestablish homeostasis and regulate the neuroinflammatory response that, if left unchecked results in exaggerated inflammation. We will test the role of a neuronal-leukocyte intracellular communication network driven by CO using neuron and macrophage specific cre-lox-hmox-1 mice to address the role of endogenous CO in comparison to exogenously-delivered CO to rescue the null phenotype. The integration between the immune system and neurological systems are key aspects of our proposal. It is speculated that the mental retardation that has been documented in the hmox-1 deficient human (and likely the mouuse) is in part related to the altered immune response existing in an uncontrolled dysregulated state driven by the lack of hmox-1 and CO.
