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

将扩张型心肌病（DCM）基因突变转化为心肌病表型的精确信号级联反应尚不清楚，但对于开发新的治疗策略具有重要意义。在我们试图进一步定义整合素连接激酶（ILK）信号传导相关扩张型心肌病的分子病理学并评估其可药物性的过程中，在本研究项目的第一个资助期，我们确定了ILK相互作用蛋白粘附素/ß-Parvin和PINCH在通过保证IPP （ILK- parvin -PINCH）复合物稳定性和IPP复合物介导的蛋白激酶B （PKB）信号传导来控制心脏收缩性方面的关键作用。值得注意的是，ipp复杂性心力衰竭斑马鱼的心脏收缩能力可以通过过度表达组成活性PKB或特异性激活心脏中PKB的化合物来恢复，这意味着PKB是治疗ipp复杂性心力衰竭的新治疗靶点。此外，我们的心脏ILK相互作用组研究揭示了一种新的ipp复合物，因此不依赖于pkb的信号通路，即所谓的fak复合物。在第二个资助期，我们现在的目标是(1)阐明ipp复合物独立的ILK途径组分在体内的作用，(2)通过系统生物学方法破译ipp复合物依赖和ipp复合物独立的心力衰竭的共同分子决定因素/网络组分和枢纽。(3)使用已经建立的ILK转基因斑马鱼系特异性分析ILK激酶活性与心功能的相关性；最后(4)在我们建立的筛选平台上，通过对ipp复合物依赖的斑马鱼心力衰竭突变体进行高通量体内小化合物筛选，确定新的潜在心力衰竭治疗方法。

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.