The molecular role of selected circRNAs in cardiac macrophage dynamics and inflammatory response during cardiac remodeling after myocardial infarction

选定的circRNA在心肌梗死后心脏重塑过程中心脏巨噬细胞动力学和炎症反应中的分子作用

• 批准号: 465131031
• 负责人: Dr. Mira Jung, Ph.D.
• 金额: --
• 依托单位: Department of Biology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/465131031?language=en
• 关键词: molecular; role; selected; circRNAs; cardiac

About one in four myocardial infarction (MI) patients progress to develop congestive heart failure, which has a 50% 5-year mortality rate. Macrophages, besides their role in host defense and tissue homeostasis, are critical players in the pathophysiological processes induced by MI. Over the MI time course macrophages undergo polarization state dynamics along with numerous changes in transcriptomic signatures. Macrophage polarization is highly referred as a therapeutic target for several cardiac diseases including MI. Importantly the transcriptomic changes include dysregulation of non-coding RNAs (ncRNAs) as well. NcRNAs are a class of RNAs which does not translate into proteins and belongs to large extent to our genome, while ncRNAs a not well studied. Circular RNAs (circRNA) are a novel type of ncRNAs formed by covalent linking between 3’ and 5’ ends. The highly conserved character of circRNAs makes them an attractive source for novel molecules to regulate gene expressions as well as disease-associated biological processes. Recently, first studies reported strong correlation between circRNAs and cardiac diseases. The main goal of this project is to identify and characterize circRNA biogenesis and functions in macrophages during cardiac remodeling post-MI. Our preliminary results demonstrate that the circRNA cHIPK2 is strongly associated with macrophage polarization, especially increased in pro-inflammatory phenotype. Accordingly, we hypothesize that modulation of cHIPK2 polarizes macrophages and associated microenvironment towards favorable anti-inflammatory phenotype, which eventually leads to an improved healing procedure post-MI. The central hypothesis will be tested with 3 specific aims. Aim 1 will examine the impact of cHIPK2 on macrophages and identify the related interaction partners in vitro. Aims 2 and 3 will explore the interconnections between cHIPK2-modulated macrophages and cardiac remodeling post-MI in vivo and in living human cardiac tissue. This proposal will dissect cHIPK2 molecular mechanisms in macrophage polarization and therapeutic applicability of cHIPK2 modulated macrophages as a novel therapeutic approach to improve post-MI healing. Overall, our project will bring new insights into new therapeutic strategies for patients with MI.

大约四分之一的心肌梗塞（MI）患者发展出充血性心力衰竭，其5年死亡率为50％。巨噬细胞除了在宿主防御和组织体内稳态中的作用外，在MI引起的病理生理过程中都是关键参与者。在MI时间过程中，巨噬细胞经历了极化状态动力学以及转录组特征的许多变化。巨噬细胞极化高度称为多种心脏病在内的治疗靶标。重要的是，转录组的变化也包括非编码RNA（NCRNA）的失调。 NCRNA是一类RNA，不转化为蛋白质，在很大程度上属于我们的基因组，而NCRNA则是研究不善的。圆形RNA（CIRCRNA）是一种新型的NCRNA，由3'和5'端之间的共价链接形成。 CircrNA的高度保守特征使它们成为调节基因表达以及与疾病相关的生物过程的新分子的有吸引力的来源。最近，第一项研究报告了CircrNA和心脏病之间的密切相关性。该项目的主要目的是识别和表征心脏重塑期间MI期间巨噬细胞中的Circrna生物发生和功能。我们的初步结果表明，circrna chipk2与巨噬细胞极化密切相关，尤其是促炎表型的增加。彼此之间，我们假设CHIPK2的调节使巨噬细胞和相关的微环境偏向于有利的抗炎表型，这有时会导致MI后改善的愈合过程。中央假设将以3个特定目的进行检验。 AIM 1将检查CHIPK2对巨噬细胞的影响，并在体外识别相关的相互作用伙伴。 AIM 2和3将探索chipk2调节的巨噬细胞与体内MI后心脏重塑之间的互连。该建议将在巨噬细胞极化和CHIPK2的治疗适用性中剖析Chipk2分子机制，以调制巨噬细胞作为一种新的治疗方法，以改善MI后愈合。总体而言，我们的项目将为MI患者带来新的见解。