Modulation of Cx43 Expression and Targeting of the Myocardial Scar (C14 (P14))

• Subject Area: Anatomy and Physiology ; Cardiac and Vascular Surgery
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 422681845

We will investigate the mechanisms underlying arrhythmia protection by Cx43 overexpression (OE) in cardiomyocytes or non-myocytes in transgenic mouse models, using ex vivo optical voltage mapping and cellular recordings in cardiac slices. This will be complemented by high-resolution 3D imaging and electron microscopy to evaluate the formation of gap junctions. A potential additive functional effect of cardiomyocyte and myo-fibroblast Cx43 OE on VT protection will be tested by crossing the two mouse lines. The impact of selective Cx43 OE in border zone cardiomyocytes will be probed using a recently reported AAV-based targeting approach. Given the embryonic lethality of constitutive Cx43 OE in cardiomyocytes, we will investigate the role of Cx43 in murine heart and human cardiomyocyte development, using transgenic mice, and 2D or 3D in vitro differentiation of human iPSC. To further improve the in vivo targeting of interventions to cardiac lesions, we will transduce myo-fibroblast in vitro and introduce them into cardiac scars using magnetic nanoparticles and magnetic steering. This will be combined with strategies to improve scar formation and cell engraftment by inhibition of the NRLP3 inflammasome or IL-1 receptor activity. For translational purposes, we will test (lenti)virus-free approaches to improve the transduction efficiency of porcine and human cardiac myo-fibroblasts. The best strategy will then be tested ex vivo by perfusing pig hearts with control and Cx43 OE virus, and performing read-outs in live tissue slices cultured for one week. Ultimately, we expect to develop a biological anti-arrhythmic approach, as well as methods to efficiently target and improve the cardiac scar.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1425: Heterocellular Nature of Cardiac Lesions: Identities, Interactions, Implications
• Applicant Institution: Albert-Ludwigs-Universität Freiburg
• Project Heads: Professor Dr. Bernd Fleischmann; Privatdozent Dr. Wilhelm Röll