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.

人们对将扩张型心肌病 (DCM) 基因突变转化为心肌病表型的精确信号级联反应知之甚少，但对于新型治疗策略的开发非常重要。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药物有效性的过程中，在本研究项目的第一个资助期间，我们确定了 ILK 相互作用蛋白 Affixin/ß-Parvin 和 PINCH 在通过保证 IPP (ILK-Parvin-PINCH) 复合物稳定性和控制心肌收缩力方面的关键作用。 IPP 复合物介导蛋白激酶 B (PKB) 信号传导。值得注意的是，IPP复合体心力衰竭斑马鱼的心肌收缩力可以通过组成型活性PKB的过度表达或特异性激活心脏中PKB的化合物来恢复，这表明PKB是治疗IPP复合体相关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颖的 IPP 复合物，因此不依赖于 PKB 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）阐明独立于IPP复合物的ILK通路成分的体内作用，（2）通过系统生物学方法破译IPP复合物依赖性和独立于IPP复合物的心力衰竭的常见分子决定因素/网络成分和中枢，（3）专门剖析ILK激酶活性与心脏功能的相关性 使用已经建立的ILK转基因斑马鱼系，最后（4）通过在我们建立的筛选平台上对IPP复合物依赖性斑马鱼心力衰竭突变体进行高通量体内小化合物筛选，确定新型潜在的心力衰竭治疗方法。