CXC/CX3C chemokine receptors and PI3K-dependent signaling pathways in the pathogenesis of inflammatory cardiomyopathy

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Inflammation of myocardium is caused by pathogens such a cardiotopic viruses and non-pathogen-related inflammation (e.g. sepsis) and is associated with poor clinical prognosis (heart failure, sudden cardiac death). Although much has been achieved in the past, the underlying inflammatory mechanisms of myocarditis/inflammatory cardiomyopathy (DCMi), influencing the extent of cardiac inflammation and the prognosis of affected patients, are only incomplete understood. Inflammation of myocardium is caused by pathogens such a cardiotopic viruses and non-pathogen-related inflammation (e.g. sepsis) and is associated with poor clinical prognosis (heart failure, sudden cardiac death). Although much has been achieved in the past, the underlying inflammatory mechanisms of myocarditis/inflammatory cardiomyopathy (DCMi), influencing the extent of cardiac inflammation and the prognosis of affected patients, are incomplete understood. However, inflammatory signaling pathways are critical in the development of DCMi and identification of these mechanisms may offer novel targets to control the disease. The current project further focuses on the role of inflammatory CXC/CX3C chemokines (SDF-1, CXCL16, fractalkine), their respective receptors (CXCR4/-6/-7 and CX3CR1) and intracellular signaling in cardiomyocytes downstream of these chemokine receptors for the pathogenesis of myocarditis/DCMi.We will evaluate both in vitro (isolated cardiomyocytes) and in vivo (CVB3-induced infectious myocarditis, angiotensin II-induced DCM including titin-knock-in-model of DCM) as well as ex vivo (endomyocardial biopsies, transmural myocardial specimen in heart failure) the role of the above mentioned factors and signaling pathways in progress and development of the disease. We will further focus on the diagnostic potential of the identified novel targets and will elaborate novel therapeutic strategies to control the disease on an individualized basis.