What The rhythmic contraction of our heart is controlled by electrical impulses that travel throughout the cardiac muscle. The signal is generated by the sinus node, which can be thought of as the natural pacemaker of our heart. The question is, what it is that makes the sinus node unique, enabling it to generate a repetitive firing of electrical signals thereby ensuring the foundation for the rhythmic cardiac contraction? We aim to perform an in-depth investigation of the molecular composition of the cardiac sinus node to explain the molecular interplay that endows this particular tissue with a unique ability to generate continuous rhythmic cardiac contractions. Furthermore, the role of the sinus node in a common cardiac disease, heart failure, shall be investigated. Why The research's outcome will contribute to clarification of the molecular players underlying the rhythmic contraction of our heart, and hence form a foundation for addressing protein dysfunctionalities in sinus node pathologies and rhythm disorders. How We will characterise the unique protein expression landscape of the natural cardiac pacemaker through execution of high-resolution mass spectrometry based cardiac proteomics experiments. Sinus node and abutting atrial tissue biopsies will be collected from mice, either with healthy or failing hearts. Extracted proteins are measured by high-resolution mass spectrometry to achieve the most comprehensive cardiac proteomes that are technologically possible today. Global protein expression profiles will be analysed to identify key protein differences between sinus node and atrial biopsies, and Markov-models will be applied to evaluate findings involved in membrane voltage oscillations. Our cardiac proteomics endeavors will enable unbiased investigations of essentially all sinus node proteins. SSR This project will explain fundamental biology of pacemaker activity of our hearts and it shall use this information to explain molecular underpinnings of heart failure, which is a common, and potentially deadly, medical condition. If successful, a molecular link between sinus node function and heart failure shall be found, which may present a means for disease intervention, making the relevance to society immediately apparent.