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

• 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

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.

心脏的病理性超负荷，例如在动脉高血压、主动脉瓣狭窄或心肌梗塞期间，会引发心脏肥大并最终导致心力衰竭。在欧洲，大约有 1000 万人患有心力衰竭，其发病率和死亡率仍然很高。因此，需要新的治疗策略。 我们在之前的工作中证明，心肌细胞中的衔接蛋白 CIB1 特异性促进病理性、适应不良肥大，但不会促进生理（适应性）肥大，因为它发生在运动员中，与疾病无关。因此，小鼠 CIB1 的基因缺失可以防止病理性肥大和心力衰竭的发展。 CIB1 通过将促肥大性磷酸酶钙调磷酸酶募集到细胞膜上，在细胞膜上的特殊微域内被激活，从而促进心肌细胞生长。 在该提案中，我们的目标是建立抑制心肌 CIB1 的转化治疗概念。首先，我们希望通过基因治疗方法用短发夹 RNA (shCIB1) 下调 CIB1。为此，我们开发了一种用腺相关病毒 (AAV) 过表达 shCIB1 的策略 9。我们现在的目标是测试 AAV-shCIB1 对小鼠实验性主动脉缩窄或心肌梗死后肥厚和心力衰竭发展的影响。其次，我们的目标是确定一种化学成分，它可以中断 CIB1 和钙调神经磷酸酶的结合，从而抑制心脏肥大和心力衰竭。我们建立了一种哺乳动物双杂交测定法，可以量化 CIB1 和钙调磷酸酶之间的相互作用。在柏林莱布尼茨分子药理学研究所的帮助下，我们希望筛选 40,000 种确定的化学物质，以了解对 CIB1/钙调神经磷酸酶相互作用的抑制作用。首先将在分离的心肌细胞中测试阳性物质的抗肥厚和钙调神经磷酸酶抑制作用。我们的长期目标是将这些转化概念发展到心力衰竭患者的临床应用。

项目成果

A gene therapeutic approach to inhibit calcium and integrin binding protein 1 ameliorates maladaptive remodelling in pressure overload

抑制钙和整合素结合蛋白1的基因治疗方法可改善压力超负荷时的适应不良重塑

• DOI: 10.1093/cvr/cvy154
• 发表时间: 2018-06-20
• 期刊: Cardiovascular Research
• 影响因子: 10.8
• 作者: Andrea Grund;Malgorzata Szaroszyk;Janina K Döppner;Mona Malek Mohammadi;B. Kattih;M. Korf;A. Gigina;M. Scherr;G. Kensah;M. Jara;I. Gruh;U. Martin;K. Wollert;A. Gohla;H. Katus;O. Müller;J. Bauersachs;J. Heineke
• 通讯作者: J. Heineke