Endosomal trafficking and functions in cardiomyocytes: insights from Arf6 signaling

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The long-term vision of our research program is to better understand a fundamental trafficking mechanism that dictate how some proteins reach the surface of contractile cells from the heart, namely the cardiomyocytes. To achieve such goal, we first propose to study, by genetic manipulation of mice, how the removal of a protein named Arf6, an important regulator of protein trafficking in other cells, is impacting heart function. Cell-surface proteins affected by the removal of Arf6 will be further analysed to establish how Arf6 impacts the localization and/or degradation of these proteins and how it affects their function at the membrane of cardiomyocytes. Moreover, we will investigate the role of Arf6 in the genesis and release of cardiac-derived exosomes, which are small vesicles released by cardiomyocytes in their immediate environment and the general circulation before being uptake by other cells. Notably, we will determine how the absence of Arf6 affects the number of exosomes released by cardiomyocytes, but also their protein and miRNA content using unbiased proteomic assays and miRNA screens, respectively. Surprisingly, while this conserved communication system between cells has gained interest in the past years, the mechanisms involved in the production of these exosomes are not yet completely understood. Hence, we expect that our findings will deepen our knowledge about the cardiac endosomal and exosomal trafficking, a fundamental but still enigmatic cellular process in cardiomyocyte's biology. The discoveries originating from this research program will provide benefits to multiple individuals and groups. First, the highly qualified personnel (HQP) formed in my laboratory will benefit from a stimulating research environment. These HQP will become expert in cardiac biology, molecular signaling, genetic manipulation, and related state of the art technology, like echocardiography assessment of murine model, to address the most pressing challenges in the cardiac research field. Also, considering the growing interest in fundamental cardiovascular research and the novel aspects of this research program, we believe our discoveries will generate transposable knowledge that will lead forward the hypothesis and discoveries of other research groups in their own field of expertise.