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.
