Thursday, May 9, 2024
5/9/2024
Project Abstract / Summary Emerin (EMD) gene mutations cause Emery Dreifuss Muscular Dystrophy type I (EDMD1), a disease characterized by skeletal muscle wasting and life-threatening atrial defects. However, the mechanism of emerin dysfunction in the heart is unknown. In this proposal, I seek to understand emerin's role in human atrial cells. Emerin is a protein of the inner nuclear membrane (INM), and a component of a nuclear cytoskeletal structure known as the nuclear lamina. Investigators have thus assumed that EDMD1 arises from defects in emerin's nuclear functions. However, Emerin has been observed at two locations in cardiomyocytes (CMs); emerin also localizes to the cardiomyocyte intercalated disc (ID)—a specialized plasma membrane (PM) domain that electromechanically couples cardiomyocytes to one another. Both of emerin's observed locations are essential for CM gene regulation and biomechanics, though we do not understand emerin's role at either structure. Our understanding has been limited by 1) the lack of tools to manipulate emerin's distribution, and 2) the lack of models to study these CM-specific mechanisms. This proposal will overcome these roadblocks by manipulating emerin's localization in human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-ACMs). Until our recent discovery, we did not know how emerin localizes to the PM, which impeded our ability to test its functions there. However, we have discovered that emerin can traverse the secretory pathway through vesicular transport to the plasma membrane. We hypothesize that secretory trafficking routes emerin to the ID to perform a specific function in cardiomyocytes. To test this hypothesis, I will first engineer a model cell system to assay emerin dynamics. Emd -/- mice do not display EDMD1 phenotypes and are thus a poor model of emerin pathology. hiPSC-ACMs, however, are tractable, mutable, and applicable to human disease. I have previously identified motifs within emerin that control its trafficking. Using this knowledge, I will introduce a panel of mutants with enhanced or blocked trafficking into emerin knockout hiPSCs. Using the cell lines I generate, I will test how emerin disruption affects ACM gene regulatory networks (Aim 2) and cellular mechanics (Aim 3). By controlling emerin's secretory trafficking, I will also test how its localization at the PM or INM influences these functions. This system will illuminate emerin's fundamental roles in human atrial cardiomyocytes for the first time. By defining these mechanisms, we will better understand EDMD1 cardiac defects and open the door to new potential therapies.
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