The role of CO/Heme-oxigenase-1-mediated signaling in normal and inflamed brain tissue

• Applicant: Dr. Florian Sieglitz
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Cell Biology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 267640975

Oxidative stress induced by reactive oxygen and nitrogen species (ROS/RNS) constitutes a fundamental threat to cells. To circumvent subsequent protein-, DNA- and lipid damage, cells require redox signaling. This machinery senses oxidative stress and induces cellular redox adaptation. One such adaptation mechanism is comprised by heme-oxygenases. By degradation of free heme and the release of carbon monoxide (CO), heme-oxygenases initiate complex ROS and RNS-mediated signaling cascades leading to redox adaptation. Key to CO signaling is its binding to heme-containing proteins which alters protein function. Accumulating evidence suggests that redox signaling plays a major role during inflammatory processes in the brain. Despite recent achievements, the cell biology of CO-mediated signaling during brain function remains poorly understood. To address the role of CO in the normal and in the inflamed brain, I propose a combination of live imaging and biochemical analyses. The live imaging approach will be guided by the recent development of fluorescent probes for ROS/RNS, CO, nitrogen oxide and cGMP detection which are well established in the host lab. In vivo detection of these signaling molecules in living brain tissue upon genetically and chemically modified CO levels will allow me to address cell type specific signaling events. To further investigate CO-mediated neural adaptation mechanisms, I will conduct a comprehensive biochemical analysis based on mass spectrometry in which different neural cell types will be addressed. My studies will lead to a better understanding of CO signaling in the brain and flatten the path towards cell type specific targeting of CO signaling during neurological dysfunction.

• DFG Programme: Research Fellowships
• International Connection: Portugal
• Host: Professor Dr. Gonçalo J. L. Bernardes