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

心肌炎症是由病原体引起的，如心位病毒和非病原体相关炎症（如败血症），并与临床预后不良（心力衰竭、心源性猝死）相关。虽然过去已经取得了很多成果，但对心肌炎/炎症性心肌病（DCMi）的潜在炎症机制，影响心脏炎症的程度和患者的预后，还不完全了解。心肌炎症是由病原体引起的，如心位病毒和非病原体相关炎症（如败血症），并与临床预后不良（心力衰竭、心源性猝死）相关。尽管过去已经取得了很多成果，但心肌炎/炎症性心肌病（DCMi）影响心脏炎症程度和患者预后的潜在炎症机制尚不完全清楚。然而，炎症信号通路在DCMi的发展中至关重要，这些机制的鉴定可能为控制该疾病提供新的靶点。目前的项目进一步关注炎性CXC/CX3C趋化因子（SDF-1、CXCL16、fractalkine）、它们各自的受体（CXCR4/-6/-7和CX3CR1）以及这些趋化因子受体下游心肌细胞内信号传导在心肌炎/DCMi发病机制中的作用。我们将在体外（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titin敲入模型）以及离体（心内膜活检，心力衰竭的跨壁心肌标本）评估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，以在个性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.