The calcium and integrin binding protein (CIB)1 as therapeutic target in heart failure

钙和整合素结合蛋白 (CIB)1 作为心力衰竭的治疗靶点

基本信息

批准号：
319937607
负责人：
Professor Dr. Jörg Heineke
金额：
--
依托单位：
European Center for Angioscience (ECAS)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/319937607?language=en
关键词：
calcium integrin binding protein CIB

项目摘要

Pathological overload of the heart for example during arterial hypertension, aortic valve stenosis or myocardial infarction triggers cardiac hypertrophy and ultimately heart failure. In Europe around 10 million people suffer from heart failure, which is still associated with high morbidity and mortality. Therefore, new therapeutic strategies are needed. We demonstrated in our previous work that the adaptor protein CIB1 in cardiomyocytes specifically promotes pathological, maladaptive hypertrophy, but not physiological (adaptive) hypertrophy as it occurs for example in athletes, where it is not associated with disease. Consequently, genetic deletion of CIB1 in mice protects against the development of pathological hypertrophy and heart failure. CIB1 promotes cardiomyocyte growth by recruiting the prohypertrophic phosphatase calcineurin to the cell membrane where it can get activated within a specialized microdomain. Within this proposal we aim to establish translational therapeutic concepts to inhibit CIB1 in the myocardium. First, we want to downregulate CIB1 with a short-hairpin RNA (shCIB1) in a gene-therapeutic approach. For this purpose we developed a strategy to overexpress shCIB1 with an adeno-associated virus (AAV) 9. We now aim to test the effects of AAV-shCIB1 on hypertrophy and heart failure development after experimental aortic constriction or myocardial infarction in mice. Secondly, we aim to identify a chemical component that interrupts the association of CIB1 and calcineurin and consequently inhibits cardiac hypertrophy and heart failure. We established a mammalian two-hybrid assay that allows quantification of the interaction between CIB1 and calcineurin. With the help of the Leibniz Institute of Molecular Pharmacology in Berlin we want to screen 40.000 defined chemical substances for an inhibitory effect on the CIB1/calcineurin interaction. Positive substances will be tested for their antihypertrophic and calcineurin inhibiting effects at first in isolated cardiomyocytes. Our long-term goal is to develop these translational concepts towards clinical application in patients with heart failure.

心脏的病理超负荷，例如在动脉高血压，主动脉瓣狭窄或心肌梗塞期间触发心脏肥大，最终会触发心力衰竭。在欧洲，约有1000万人患有心力衰竭，这仍然与高发病率和死亡率有关。因此，需要新的治疗策略。我们在以前的工作中证明了心肌细胞中的衔接蛋白CIB1专门促进病理，适应不良的肥大，但不能像在运动员中发生生理（适应性）肥大，因为它与疾病无关。因此，小鼠中CIB1的遗传缺失可以防止病理肥大和心力衰竭的发展。 CIB1通过募集亲身性磷酸酶钙调蛋白到细胞膜来促进心肌细胞的生长，在该细胞膜中可以在专门的微域中被激活。在此提案中，我们旨在建立转化治疗概念以抑制心肌中的CIB1。首先，我们希望以一种基因治疗方法的短发RNA（SHCIB1）下调CIB1。为此，我们制定了一种用腺相关病毒（AAV）9过表达SHCIB1的策略。我们现在旨在测试AAV-SHCIB1对小鼠实验性主动脉收缩或心肌梗死后肥大和心力衰竭发育的影响。其次，我们旨在确定一种上断CIB1和钙调神经蛋白关系的化学成分，从而抑制心肥大和心力衰竭。我们建立了一种哺乳动物的两杂化测定法，该测定法可以定量CIB1和钙调蛋白之间的相互作用。在柏林莱布尼兹分子药理学研究所的帮助下，我们希望筛选40.000个定义的化学物质，从而对CIB1/钙调神经酶相互作用产生抑制作用。阳性物质将在孤立的心肌细胞中首先测试其抗肿瘤和钙调蛋白抑制作用。我们的长期目标是将这些转化概念发展为心力衰竭患者的临床应用。