Novel Signaling Mechanism in Chamber-Specific Postnatal Heart Growth

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Project Summary Chamber specific postnatal growth is the cornerstone of postnatal heart development, however, the underlying molecular mechanisms are almost entirely unexplored. In preliminary studies, we analyzed and compared key intracellular signaling activities between LV and RV in neonatal mouse hearts and discovered that p38 MAP kinase activation displayed a unique chamber-specific and developmental stage specific pattern in RV during neonatal to adolescent transition. Strikingly, cardiomyocyte specific inactivation of p38 activity in the developing mouse heart led to lethal cardiomyopathy associated with RV specific induction of myocyte proliferation and hypertrophy in neonatal mouse heart while the LV was minimally affected. Furthermore, IRE1α- Xbp1 axis is essential downstream signaling in p38 mediated regulation of cardiomyocyte proliferation. Taken together, these findings reveal for the first time that two previously established pathogenic stress-related signaling pathways, p38 MAPK and IRE1α/Xbp1, are also indispensable players in normal chamber specific development in postnatal heart during fetal to adult transition. In this proposal, we aim to explore this novel finding by accomplishing the following three specific aims. Aim 1): Determine the functional and molecular impact of IRE1α/Xbp1 axis in chamber-specific postnatal heart development using novel mouse models with targeted manipulation of IRE1α/Xbp1 activity. 2) Establish the specific contribution IRE1α/Xbp1 axis in p38 mediate regulation of chamber-specific growth during postnatal heart development. 3) Uncover downstream targets underlying chamber specific regulation of p38/IRE1α/Xbp1 signaling in postnatal heart. These studies will establish for the first time an intracellular signaling network for chamber-specific postnatal development in neonatal heart and fill a critical gap in our current knowledge in this important area of cardiac biology.