RBPMS, a novel RNA splicing regulator of cardiac function and disease - Project Summary/Abstract Cardiovascular disease is the leading cause of mortality in the US and worldwide. Decades of endeavors in studying cardiovascular disease have led to a substantial understanding of underlying mechanisms, but there is still much to be learned. Cardiovascular homeostasis is regulated at both transcriptional and posttranscriptional levels, and an increasing body of evidence suggests that RNA posttranscriptional modifications, such as alternative RNA splicing, play essential roles in regulating cardiac function and disease. A previous study by the applicant (Dr. Peiheng Gan) has revealed that RNA-binding protein with multiple splicing (RBPMS) is crucial for cardiomyocyte proliferation and heart development through modulating alternative RNA splicing. In the new study, the applicant found that RBPMS is required for adult cardiac contractility. The absence of RBPMS impaired cardiomyocyte contractility and impacted the splicing of various sarcomeric genes, which displayed distinct patterns. Cardiac RBPMS expression was decreased in patients with heart failure and doxorubicin-induced heart failure in animal models. Intriguingly, the overexpression of RBPMS showed protective effects on contractility and survival in doxorubicin-treated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Together, these data suggest that RBPMS is a key regulator of adult heart function and heart failure progression. During the K99 phase of this proposal (Aim 1), the applicant will characterize how RBPMS regulates cardiomyocyte contraction through modulating RNA splicing using both mouse models and hiPSC-CMs. In Aim 2, the applicant will leverage cellular and molecular tools to characterize the functional interactions between RBPMS and other cardiac RNA binding proteins (RBPs), including RBM20 and RBFOX1. This study provides the applicant with a unique opportunity to investigate how different RBPs interact to regulate cardiac function and alternative RNA splicing. During the R00 phase (Aim 3), the applicant will explore the therapeutic potential of overexpressing RBPMS in doxorubicin-induced mouse heart failure and determine the molecular mechanisms of RBPMS-mediated protective effects. The completion of the proposed study will provide critical insights into the posttranscriptional regulation of cardiac function by RBPs and create new opportunities for curing cardiovascular disease. The applicant will acquire crucial knowledge and skills by studying RBPs and RNA posttranscriptional modifications during his K99 phase to complement his previous expertise in cardiovascular research. Additionally, the applicant’s career development will be enhanced by the expertise of an exceptional mentoring and advisory committee, as well as the unparalleled resources and ample educational and training opportunities at UT Southwestern Medical Center, a world-class research institution. The outstanding mentoring, unmatched resources, and strong commitment from his department will strengthen the applicant’s candidacy for and transition to an independent tenure-track faculty position.
