Defining the role of kynurenine pathway metabolites in the inflammatory response to trypanosome invasion of the CNS. (360G-Wellcome-094691_Z_10_Z)

This project will define the role of the kynurenine pathway in generating the neuroinflammatory response in a mouse model of human African trypanosomiasis (HAT), also known as sleeping sickness. Recent findings in our laboratories using a kynurenine-3-monooxygenase (KMO) inhibitor have demonstrated the neuropathogenic importance of this metabolic pathway in generating the more severe form of CNS inflammatory response to trypanosomes. Our core hypothesis is that kynurenine pathway catabolites ar e key determinants of the CNS inflammatory response to trypanosome invasion. This is of importance for both a better understanding of HAT neuropathogenesis and a potential new mode of adjunctive treatment for late-stage disease. The proposal will address the following questions: 1. Does KMO inhibition alter the concentration of kynurenine metabolites or inflammatory mediators within the brain? 2. Do changes in the concentrations of kynurenine pathway metabolites and key inflammatory media tors correlate with BBB function as assessed by MRI? 3. Is the severity of CNS inflammation and BBB breakdown reduced or abrogated in KMO knockout mice? 4. Does treatment with a SP receptor antagonist enhance the reduction in CNS inflammation in KMO -/- mice compared with wild-type animals? 5. Are kynurenine pathway metabolites potential markers for disease staging?