Mekanistiska studier av dyssynkroni och resynkronisering för att identifiera nya molekylära mål för läkemedelsbehandling och biologiska biomarkörer vid hjärtsvikt

Bakgrund:

A dyssynchronous activation and contraction pattern accelerates disease progression in failing heart. Cardiac Resynchronization Therapy (CRT) reduces mortality in heart failure but its cellular and molecular mechanisms remains elusive. CRT is a unique heart failure therapy in the sense that it acutely improves hemodynamics and also reduces mortality in the long term.

Therefore, CRT can serve as a model for successful heart failure therapies. We have recently developed a mouse pacemaker enabling studies of CRT-biology in a genetically modifiable animal for the first time. Målsättning:

The overall aim of this project is to "reverse-engineer" CRT to novel heart failure pharmacological therapies by dissecting its cellular and molecular effects. Specific aims are to test the hypothesis that resychronization enhances sarcomere Ca2+ sensitivity, deactivates the transcription factor CREB, reduces IL-6-Notch 3 signalling and normalizes dyssynchrony-induced heterogeneity in mRNA expression. Also, we aim at discovering novel protein- and lncRNA biomarkers associated with resynchronisation.

Arbetsplan:

Three groups of mice will be followed for four weeks after induction of heart failure by schema reperfusion: sinus rhythm (synchronous heart failure), right ventricular pacing (dyssynchronous heart failure) and two weeks of right ventricular pacing followed by two weeks sinus rhythm (resynchronized heart failure). Mice cardiac tissue will be examined with a variety of biochemical anlaysis (western blots, PCR, RNA-sequencing, kinase activity kits etc) to address hypothesis outlined in the aims section.

Blood samples from patients before and six months after CRT implantation will be analyzed for protein biomarkers and exosomal long non-coding RNAs and compared to data from the mouse-pacemaker model. Betydelse:

We aim at dissecting the exact biological mechanisms responsible for CRTs salutary effects in order to detect novel molecular targets for drug discovery in heart failure. Also, discovery of novel biomarkers may help patient selection for CRT. Improvement in care for patients with heart failure is important since it is a common and life threatening disease.