FRIMEDBIO-Fri prosj.st. med.,helse,biol

The World Health Organisation predicts that oxygen-related diseases of the brain and heart (i.e. anoxia/ischemia) will be the leading cause of mortality across the world by the year 2020. The EU healthcare cost of cerebral ischemia alone was estimated to be over 31 billion Euro in 2003. Consequently, understanding mechanisms for ischemic injury and establishing novel therapies for effective protection against ischemia is of paramount importance to researchers and clinicians. This project has focus on isc hemic heart disease. Innate immunity is our first line of defence against invading microorganisms. It is present from birth and consists of phagocytosing cells and their mediators. The cells recognize conserved motifs in bacteria and viruses called patho gen associated molecular patterns (PAMPs). The innate immune system can also recognize endogenous motifs, termed damage associated molecular patterns (DAMPs). Polly Matzinger proposed that the immune system does not discriminate between self and non-self, but reacts upon danger rather than foreignness. DAMPs are intracellular components. PAMPs and DAMPs are recognized by pattern recognition receptors, of which Toll Like Receptors (TLR) are the most studied family. Another family are the Nod-like receptor family. Mitochondria are evolutionary endosymbiots derived from bacteria containing their own DNA (mtDNA), which, similar to bacterial DNA is rich in unmethylated CpG motifs. We propose that mtDNA may serve as an endogenous danger signal, causing sterile inflammation in the heart during ischemia signaling through toll-like receptor 9 and nuclear factor kappa B. We also propose that mtDNA is injured in myocardial ischemia, and that mtDNA repair enzymes are crucial for cardiac repair after injury. We want t o study Nod-like receptor signalling in the heart, and identify possible endogenous ligands for them. Finally, we propose that there may be a gender-difference in mtDNA damage and repair.