PR000427 (Project)

Description:Cardiomyopathy is the most common cause for sudden death and heart failure with tremendous public health burden in the U.S. Accumulating evidence from both animal models and clinical studies in human transplant patients suggests that partial inhibition of mechanistic Taget of Rapamycin (mTOR) signaling is a viable avenue for therapeutic intervention. Specifically, we recently showed both compound (rapamycin) treatment and genetic manipulation using a mechanistic Target of Rapamycin (mTOR) haploinsufficient (mTOR+/-) mutant confers cardiac protection against cardiomyopathies of two different etiologies in zebrafish. Mechanistically, antihypertrophy, anti-apoptosis and proautophagy of mTOR inhibition play important roles in this cardioprotection process. Our central hypothesis is that this mTOR inhibition-mediated cardioprotection is conferred by transcription factor EB (TFEB)-regulated autophagy activation. To test this hypothesis, we propose to pursue a systematic metabolite profiling analysis in the heart upon DOX stress under fine-tuned mTOR inhibition. We expect to define metabolite signatures in different types of cardiomyopathy, metabolite signature for the cardioprotective effects of mTOR inhibition, as well as metabolite signatures for TFEB genetic manipulations. These data will be compared with transcriptome studies to prove functions of TFEB signaling in cardioprotective effects of mTOR inhibition, which shall provide a solid foundation for renewing our current RO1 grant aiming to develop mTOR-based therapy for heart failure.