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

• Applicant: Mira Jung, Ph.D.
• Subject Area: Cardiology, Angiology ; General Genetics and Functional Genome Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465131031

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.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Professor Sebastian Kadener, Ph.D.
• Co-Investigators: Professor Dr. Achim Aigner; Professor Dr. Nico Lachmann; Filippo Perbellini, Ph.D.; Professor James Thackeray, Ph.D.