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
基本信息
- 批准号:465131031
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:
- 资助国家:德国
- 起止时间:
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
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死 (MI) 患者会发展为充血性心力衰竭,其 5 年死亡率为 50%。 巨噬细胞除了在宿主防御和组织稳态中发挥作用外,还在 MI 诱发的病理生理过程中发挥着关键作用。在心肌梗死的过程中,巨噬细胞经历极化状态动态以及转录组特征的大量变化,巨噬细胞极化被高度认为是包括心肌梗死在内的多种心脏病的治疗靶点。转录组变化还包括非编码 RNA (ncRNA) 的失调,NcRNA 是一类不翻译成蛋白质的 RNA,在很大程度上属于我们的基因组,而 ncRNA 则尚未得到充分研究。通过 3' 和 5' 末端共价连接形成的新型 ncRNA,circRNA 的高度保守特性使其成为调节基因表达以及疾病相关的新型分子的有吸引力的来源。最近,第一个研究报告了 circRNA 与心脏病之间的密切相关性,该项目的主要目标是鉴定和表征 MI 后心脏重塑过程中的 circRNA 生物发生和功能。与巨噬细胞极化相关,尤其是促炎表型的增加因此,我们发现 cHIPK2 的调节使巨噬细胞和相关微环境向有利的抗炎表型极化,最终改善愈合过程。中心假设将通过 3 个具体目标进行检验,目标 1 将检查 cHIPK2 对巨噬细胞的影响,并确定体外相关的相互作用伙伴,目标 2 和目标 3 将探索 cHIPK2 调节的巨噬细胞与心脏重塑之间的相互关系。该提案将剖析 cHIPK2 在巨噬细胞极化中的分子机制以及 cHIPK2 调节巨噬细胞作为一种新型的治疗适用性。总体而言,我们的项目将为心肌梗死患者的新治疗策略带来新的见解。
项目成果
期刊论文数量(0)
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Dr. Mira Jung, Ph.D.其他文献
Dr. Mira Jung, Ph.D.的其他文献
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