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

心肌炎症是由病原体如心脏病毒和非病原体相关的炎症（例如败血症）引起的，并且与不良临床预后（心力衰竭、心源性猝死）相关。虽然在过去已经取得了很大的成就，心肌炎/炎性心肌病（DCMi）的潜在炎症机制，影响心脏炎症的程度和受影响患者的预后，只是不完全了解。心肌炎症是由病原体如心脏病毒和非病原体相关的炎症（例如败血症）引起的，并且与不良临床预后（心力衰竭、心源性猝死）相关。虽然在过去已经取得了很大的成就，心肌炎/炎性心肌病（DCMi）的潜在炎症机制，影响心脏炎症的程度和受影响的患者的预后，是不完全了解。然而，炎症信号通路在DCMi的发展中至关重要，并且这些机制的鉴定可能提供控制疾病的新靶点。目前的项目进一步关注炎症CXC/CX3C趋化因子的作用，（SDF-1，CXCL 16，fractalkine），它们各自的受体在心肌炎/DCMi的发病机制中，趋化因子受体CXCR4/-6/-7和CX3CR1与心肌细胞中这些趋化因子受体下游的细胞内信号传导。（分离的心肌细胞）和体内（CVB3诱导的感染性心肌炎，血管紧张素II诱导的DCM，包括DCM的肌联蛋白敲入模型）以及离体（心肌内膜活检，心力衰竭的透壁心肌标本）上述因素和信号通路在疾病进展和发展中的作用。我们将进一步关注已确定的新靶点的诊断潜力，并将制定新的治疗策略，以在个体化的基础上控制疾病。

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.