The role of PIDDosome in cardiomyocyte ploidy control

The biological function of pumping blood through the entire body depends on the continuous contractile capability of cardiomyocytes, a special type of muscle cell present in our heart. Cardiomyocytes stop proliferating shortly after birth, and increase their genomic information by duplicating their DNA content entering a state called polyploid. Myocardial infarction, commonly known as heart attack, is characterized by a loss of cardiomyocytes generating an unbalanced blood flow. One possible cure to the long-term consequences of heart attacks is to re-activate cardiomyocyte proliferation. However, polyploidy and the post-mitotic status of mature adult cardiomyocytes, are a barrier for restoring heart function after myocardial infarction. Therefore, understanding the mechanisms regulating cardiomyocyte maturation is fundamental for heart regeneration. Recent studies in our laboratory have proven that a protein complex, dubbed the PIDDosome, controls p53, a key-regulator of proliferation in all dividing cells. Through this ability, the PIDDosome is needed to limit desired, as well as accidental polyploidization events in our body during organ development after birth. This has been studied in detail in the context of liver growth and regeneration, identifying this protein complex as a potential target to improve liver growth after damage. Since PIDDosome function in the heart has not yet been investigated, but we have reason to believe that it exerts a function similar to that in the liver, the overall goal of this project is to unveil whether, when and how the PIDDosome activates a cardiomyocyte-specific genetic program in the heart that limits cardiomyocyte polyploidization during organ growth. Thereby, it may also impose a barrier to heart regeneration after injury. In detail, we will define the timing of PIDDosome activation and function, as well as the dynamic regulation of PIDDosome expression during heart development after birth and after injury. Moreover, we plan to determine the program imposed by the PIDDosome to limit cardiomyocyte growth using cutting-edge technologies, allowing us to interrogate the changes in the number and type of genes and proteins that are active in the heart. At the same time, we intend to identify factors through which the PIDDosome prevents the proliferation of cardiomyocytes and hopefully also means to reverse this blockade to facilitate heart regeneration.