SFB 1116: Master switches in cardiac ischemia

CRC 1116“心脏缺血中的主开关”的基本和前瞻性目标是确定新的靶点，即对心肌缺血的急性和亚急性反应至关重要的分子、途径和机制，我们将其定义为“主开关”。重要的是，CRC 1116考虑了缺血性心脏损伤和全身炎症反应、代谢共病(肥胖、胰岛素抵抗、2型糖尿病(T2 DM))和贫血的系统性串扰。CRC1116分为两个概念领域。A组“细胞内和细胞内效应物”将涉及心肌缺血病理生理反应的关键方面，如离子通道重塑、远隔心肌的肌节功能、p27和端粒酶逆转录酶(TERT)在线粒体中的作用、血小板聚集以外的功能、生长因子信号和G蛋白偶联信号的调节剂及其对免疫细胞和心肌细胞反应的作用，以及深入分析富含透明质酸基质的保护功能。B组的项目涉及(I)调节心肌缺血后炎症反应的机制，如腺苷-白介素6轴和共刺激分子，以调节T细胞反应(Ii)胰岛素抵抗、肥胖和T2 DM患者的混合作用的潜在机制，迄今尚不清楚的棕色脂肪组织和1-磷酸鞘氨醇在心肌缺血和T2 DM中的作用。通过在大型动物模型中研究T2 DM对远程缺血条件作用的混杂效应，有望获得潜在的临床应用。使用翻译方法，将在患者中研究胰岛素抵抗、伴有异位脂肪沉积的非酒精性脂肪性肝病以及T2 DM对ST段抬高心肌梗死(STEMI)的影响。因此，CRC1116将提供新的靶点(主开关)和/或治疗选项，考虑到由共病和其他系统干扰确定的特定病理生理环境。在心脏缺血后的急性期和亚急性期识别这些“主开关”将有助于更好地对患者进行有针对性的治疗，并最终对他们的长期结果产生积极影响。

The fundamental and prospective aim of the CRC 1116 “Master switches in cardiac ischemia” is to identify new targets, i.e. molecules, pathways and mechanisms that are critical for the acute and subacute response to myocardial ischemia, which we define as “master switches”. Importantly, the CRC 1116 considers systemic cross talk of ischemic cardiac injury and systemic inflammatory responses, metabolic comorbidities (obesity, insulin resistance, type 2 diabetes (T2DM)) and anemia. The CRC 1116 is organized into two conceptual areas. Project group A, “Intracellular and Cellular Effectors”, will address key aspects of pathophysiologic responses to cardiac ischemia such as ion channel remodeling, sarcomere function in the remote myocardium, role of p27 and telomerase reverse transcriptase (TERT) in mitochondria, platelet functions beyond aggregation, growth factor signaling and modulators of G-protein coupled receptor signaling and their role for immune cell responses and cardiac myocyte responses, respectively, as well as in-depth analysis of the protective function of cardiac hyaluronan-rich matrix.In project group B “Metabolic Effectors and Systemic Interference” the focus lies on the complex cross talk between infarct healing and cardiac adaptation and systemic effector systems and comorbidities. The projects in project group B address (i) mechanisms regulating the inflammatory response after cardiac ischemia such as the adenosine-interleukin-6 axis and co-stimulatory molecules to modulate T cell responses (ii) mechanisms underlying the confounding effects in patients with insulin resistance, obesity and T2DM, the so far unknown role of brown adipose tissue and of sphingosine 1 phosphate in myocardial ischemia and T2DM. Potential clinical translation is expected from investigating the confounding effects of T2DM on remote ischemic conditioning in a large animal model. Using translational approaches the impact of insulin resistance, non-alcoholic fatty liver disease with ectopic lipid deposition and of T2DM in ST elevation myocardial infarction (STEMI) will be studied in patients. Thereby the CRC1116 will provide new targets (master switches) and/or treatment options taking into account the specific pathophysiological context determined by comorbidities and other systemic interferences. The identification of these “master switches” in the acute and subacute phase after cardiac ischemia will be useful to better stratify patients to targeted therapies and ultimately positively affect their long-term outcome.