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目前还知之甚少，但对于开发新的治疗策略具有极其重要的意义。为了进一步确定整合素相关的扩张型心肌病(ILK)信号转导相关扩张型心肌病的分子病理学并评估其可药性，在本研究项目的第一个资助期内，我们确定了ILK相互作用蛋白Affisin/ü-Parvin和Pinch通过保证IPP(ILK-Parvin-Pinch)复合体的稳定性和IPP复合体介导的蛋白激酶B(PKB)信号转导，在控制心肌收缩能力方面发挥了关键作用。值得注意的是，IPP复合型心力衰竭斑马鱼的心肌收缩能力可以通过过表达结构性活性PKB或在心脏中特异性激活PKB的化合物来恢复，这意味着PKB可能成为治疗IPP复合型心力衰竭的新的治疗靶点。此外，我们的心脏ILK相互作用组研究揭示了一种新的IPP-复合体，从而揭示了PKB不依赖的信号通路，即所谓的FAK-复合体。在第二个资助期，我们的目标是(1)阐明IPP依赖的ILK通路组件在体内的作用；(2)通过系统生物学的方法破译IPP依赖和IPP依赖的心力衰竭的常见分子决定因素/网络组件和中心；(3)利用已建立的ILK转基因斑马鱼株系，具体剖析ILK_S激酶活性与心功能的相关性；以及(4)在我们建立的筛选平台上，通过高通量体内小分子化合物筛选来筛选IPP依赖的斑马鱼心力衰竭突变体，从而确定潜在的治疗心力衰竭的新药物。

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.