In comparison to the advances in the medical treatment of adult heart failure over the past 50 years, relatively little progress has been made in the treatment of pediatric dilated cardiomyopathies (DCM). While the majority of pediatric DCM cases are considered idiopathic, genetic etiologies are commonly suspected. Pediatric DCM has a poor prognosis, particularly for infants < 1-year-old. Drug development efforts for pediatric heart failure have been hampered by the lack of understanding of disease pathophysiology. Against this backdrop, our lab recently identified the RTTN gene, encoding the centrosome protein Rotatin, as a new causal gene for nonsyndromic congenital dilated cardiomyopathy (cDCM). Additionally, we found that impaired cardiomyocyte maturation, involving the failure to assemble perinuclear microtubule organizing center (pnMTOC), underlies the structural and functional defects observed in the mutant cardiomyocytes. Based on this finding, we hypothesize that impaired postnatal cardiomyocyte maturation, in which the primary MTOC fails to switch from the centrosome to the perinuclear region, is a new general paradigm for the pathogenesis of cDCM. Remarkably, we found that a small molecule C19 can restore cardiomyocyte maturation and reverse every feature of cDCM, including impaired pnMTOC assembly, in the induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model. To better understand the composition and the functional role of pnMTOC important for proper sarcomere alignment during cardiomyocyte maturation, we will utilize the following specific aims: 1) Determine which centrosome proteins are dependent on RTTN for perinuclear relocalization during cardiomyocyte maturation; 2) Determine which centrosome proteins play a functional role in MT cytoskeleton assembly and sarcomere alignment in mature cardiomyocytes, and 3) Elucidate the mechanism by which C19 rescues pnMTOC assembly in RTTN-/- cardiomyocytes. The proposed research is highly innovative in that it leverages the newly discovered insights to cDCM pathogenesis to develop future precision medicines with a transformational impact on the lives of infants with this devastating illness.