Regenerating the cardiac pacemaker and conduction system by reprogramming
Projectomschrijving
In Nederland worden jaarlijks duizenden pacemakers geïmplanteerd. Ondanks het succes van deze behandeling zijn er belangrijke tekortkomingen. Binnen dit project is onderzoek
uitgevoerd naar een oplossing voor deze tekortkomingen door de ontwikkeling van biologische pacemakers gebaseerd op een nieuw type gentherapie. Ons onderzoek heeft
nieuwe methodes geïdentificeerd voor het vervaardigen van dergelijke biologische pacemakers. Vervolg onderzoek zal zich richten op het verder optimaliseren van deze
methodes met als uiteindelijk doel deze toe te passen bij patiënten.
Verslagen
Samenvatting van de aanvraag
Cardiac fibrosis is a major cause of dysfunction of the sinoatrial node (SAN), atrioventricular node (AVN) and/or atrioventricular bundle (AVB) that generate and propagate the electrical impulse in the heart. Fibrosis may therefore precipitate disease-causing bradycardia (slow heart rates). The current standard of therapy includes the implantation of electronic pacemakers. Despite continuous efforts at improvement, these devices still harbor important limitations, including inadequate sensitivity to autonomic modulation, suboptimal hemodynamic performance, and inappropriateness for the maturing heart of a child. These limitations have stimulated development of novel approaches to treatment that rely on gene and/or cell therapies. Although remarkable progress has been made in this area, providing true structural repair of the disease-causing fibrosis is a high priority. Therefore I propose to develop reprogramming methods that reduce fibrosis by promoting transdifferentiation of cardiac fibroblasts into specific components of the pacemaker and conduction system. I will start by overexpressing combinations of transcription factors in cultured cardiac fibroblasts obtained from two different reporter mouse lines harboring a fluorescent label to trace cardiac pacemaker/conduction system cells. The initial screen will identify sets of transcription factors that have strong potential to specifically induce the following phenotypes: 1) induced (i)SAN cells, 2), iAVN cells, and 3) iAVB cells. Next, I will further improve the enforcement of these phenotypes by using small molecules and miRNAs, and explore the most promising protocol in mouse hearts with experimentally-induced myocardial infarction, and in fibroblasts of canine and human origin. By the end of this Veni-period I anticipate to have developed specific reprogramming approaches that have strong potential to locally repair the pacemaker and conduction system. Next steps will include the development of clinically-approved delivery methods and testing in canine models of bradycardia.