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Our work program consists of three specific, interconnected work packages (WP) and is strongly integrated into the CRC. The overall goal is to investigate how circular RNAs are mechanistically involved in cardiac remodeling and diastolic dysfunction. We have established and published relevant methods for cardiac phenotyping, RNA sequencing and analysis. Specifically, we aim (1) to improve our understanding about the function and potential therapeutic modulation using in vitro and ex vivo models of HFpEF, (2) to establish a new cell-type specific circRNA-based therapeutic approach of HFpEF and (3) to test whether selected circulating noncoding RNAs can serve as stratification markers in various cohorts of patients with HFpEF. The ambition and vision of this project is to develop a next generation therapeutic approach for HFpEF patients within the first funding period of the CRC and beyond.
Graphical Abstract: From mechanistic studies to therapeutic and diagnostic strategies in HFpEF using circular RNAs. Established circRNA candidates will be modulated and their therapeutic efficacy explored in vitro, ex vivo and in vivo by a range of molecular, cellular and physiological assays (WP1, WP2). By profiling a pre-identified set of secreted circRNAs in supernatant of human myocardial slices and in blood of HFpEF cohorts and by subsequent new machine learning approaches a new patient stratification panel for HFpEF subgroups will be explored.
McKinsey TA, Foo R, Anene-Nzelu CG, Travers JG, Vagnozzi RJ, Weber N, Thum T. Emerging epigenetic therapies of cardiac fibrosis and remodelling in heart failure: from basic mechanisms to early clinical development. Cardiovasc Res. 2023 Feb 3;118(18):3482-3498. doi: 10.1093/cvr/cvac142. PMID: 36004821.
Thum T. Orchestration of vascular smooth muscle cell plasticity using epigenetic therapy. Eur Heart J. 2022 Nov 14;43(43):4577-4578. doi: 10.1093/eurheartj/ehac200. PMID: 35452116.
Makarewich CA, Thum T. Exercise-Induced Long Noncoding RNAs As New Players in Cardiac Hypertrophy. Circulation. 2022 Apr 19;145(16):1234-1237. doi: 10.1161/CIRCULATIONAHA.122.059278. Epub 2022 Apr 18. PMID: 35436132; PMCID: PMC9026693.
Kreutzer FP, Meinecke A, Mitzka S, Hunkler HJ, Hobuß L, Abbas N, Geffers R, Weusthoff J, Xiao K, Jonigk DD, Fiedler J, Thum T. Development and characterization of anti-fibrotic natural compound similars with improved effectivity. Basic Res Cardiol. 2022 Mar 2;117(1):9. doi: 10.1007/s00395-022-00919-6. PMID: 35235052; PMCID: PMC8891108.
van der Velden J, Asselbergs FW, Bakkers J, Batkai S, Bertrand L, Bezzina CR, Bot I, Brundel BJJM, Carrier L, Chamuleau S, Ciccarelli M, Dawson D, Davidson SM, Dendorfer A, Duncker DJ, Eschenhagen T, Fabritz L, Falcão-Pires I, Ferdinandy P, Giacca M, Girao H, Gollmann-Tepeköylü C, Gyongyosi M, Guzik TJ, Hamdani N, Heymans S, Hilfiker A, Hilfiker-Kleiner D, Hoekstra AG, Hulot JS, Kuster DWD, van Laake LW, Lecour S, Leiner T, Linke WA, Lumens J, Lutgens E, Madonna R, Maegdefessel L, Mayr M, van der Meer P, Passier R, Perbellini F, Perrino C, Pesce M, Priori S, Remme CA, Rosenhahn B, Schotten U, Schulz R, Sipido KR, Sluijter JPG, van Steenbeek F, Steffens S, Terracciano CM, Tocchetti CG, Vlasman P, Yeung KK, Zacchigna S, Zwaagman D, Thum T. Animal models and animal-free innovations for cardiovascular research: current status and routes to be explored. Consensus document of the ESC Working Group on Myocardial Function and the ESC Working Group on Cellular Biology of the Heart. Cardiovasc Res. 2022 Dec 9;118(15):3016-3051. doi: 10.1093/cvr/cvab370. PMID: 34999816; PMCID: PMC9732557.