Integrin-linked kinase (ILK) signalling - a novel target for heart failure

整合素连接激酶 (ILK) 信号传导 - 心力衰竭的新靶标

• 批准号: 66045085
• 负责人: Professor Dr. Wolfgang Rottbauer
• 金额: --
• 依托单位: Klinik für Innere Medizin II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/66045085?language=en
• 关键词: Integrin; linked; kinase; ILK; signalling

The precise signaling cascades that translate mutations in dilated cardiomyopathy (DCM) genes into the cardiomyopathic phenotype are only poorly understood, but of immense importance for the development of novel treatment strategies. In our attempt to further define the molecular pathology of Integrin linked kinase (ILK)-signalling associated dilated cardiomyopathy and evaluate its drugability, during the first funding period of this research project we identified a crucial role of the ILK interacting proteins Affixin/ß-Parvin and PINCH in controlling cardiac contractility by warranting IPP (ILK-Parvin-PINCH) complex stability and IPP complex mediated protein kinase B (PKB)-signaling. Remarkably, cardiac contractility in IPP-complex heart failure zebrafish can be restored either by over-expression of constitutive-active PKB or compounds that specifically activate PKB in the heart, implicating PKB as a novel therapeutic target to treat IPP-complex associated heart failure. Furthermore, our cardiac ILK interactome studies revealed a novel, IPP-complex and hence PKB-independent signaling pathway, the so-called FAK-complex. In the second funding period we now aim to (1) elucidate the in vivo role of IPP-complex-independent ILK pathway components, (2) decipher the common molecular determinants/network components and hubs of IPP-complex-dependent and IPP-complex-independent heart failure by a systems biology approach, (3) specifically dissect the relevance of ILK´s kinase activity on heart function using the already established ILK-transgenic zebrafish lines and finally (4) identify novel potential heart failure therapeutics by high-throughput in vivo small compound screening on IPP-complex-dependent zebrafish heart failure mutants on our established screening platform.

将扩张心肌病（DCM）基因中的突变转化为心肌病态表型的精确信号传导级联反应仅被鲜为人知，但对于发展新型治疗策略的发展至关重要。 In our attempt to further define the molecular pathology of Integrin linked kinase (ILK)-signalling associated dilated cardiomyopathy and evaluate its drugability, during the first funding period of this research project we identified a crucial role of the ILK interacting proteins Affixin/ß-Parvin and PINCH in controlling cardiac contractility by warning IPP (ILK-Parvin-PINCH) complex stability and IPP复杂的介导的蛋白激酶B（PKB）信号。值得注意的是，IPP复合心力衰竭中的心脏收缩率可以通过过度表达的构成型PKB来恢复斑马鱼，或者可以专门激活心脏中PKB的化合物，而将PKB视为一种新型的治疗靶标，以治疗IPP-applex相关的心力衰竭。此外，我们的心脏ILK相互作用组研究揭示了一种新颖的IPP复合物，因此是PKB独立的信号传导途径，即所谓的FAK-COMPERX。在第二个资金期间，我们现在的目标是（1）阐明IPP复合物独立的ILK途径成分的体内作用，（2）解释常见的分子决定剂/网络组件和IPP - 复合物依赖性和IPP依赖性心脏失败的心脏失败的系统生物学方法（3）特定的（3）依赖于IPP - 复合物的心脏失败，（3）使用已经建立的ILK-转基因斑马鱼线，最后（4）通过在我们既定的筛查平台上的IPP复合依赖性斑马鱼心力衰竭突变体上的体内小型化合物筛选来确定新型的潜在心力衰竭治疗。