Cardiomyopathy and related heart failure affect millions of Americans. Therefore, pathway-based therapies are highly desirable. The goal of this proposal is to leverage unique genetic tools in zebrafish to elucidate cardioprotective functions of target of rapamycin (TOR) signaling and develop novel therapeutic compounds via modifier screens. There are two obstacles prohibiting modifier screens from being conducted in adult zebrafish: the lack of adult assays to analyze cardiomyopathy-like phenotypes, and the difficulty to track adult mutant fish. To address the former challenge, we established and characterized first adult fish models of cardiomyopathy, including a model induced by Doxorubicin (DOX). To address the latter challenge, we adapted a transposon-based insertional mutagenesis strategy that facilitates the identification of all mutants by a RFP tag. We have conducted both phenotype-based insertional mutagenesis screens and chemical screens, and identified gene modifiers and compound modifiers of TOR signaling that sequentially affect DOX-induced cardiomyopathy. Preliminary studies using these genetic resources suggested that activated autophagy conveys the cardioprotective function of TOR inhibition. In this proposal, we will continue to leverage zebrafish genetics to test our central hypothesis that the cardioprotective functions of TOR inhibition are conferred by the activated autophagy, which can be harnessed by modifier screens in adult zebrafish to identify novel genes and therapeutics for treating cardiomyopathy.
In Specific Aim 1, we will determine the conservation of adult zebrafish as a model organism for cardiomyopathy.
In Specific Aim 2, we will discern functions of autophagy and pS6K subpathways in cardiomyopathy via phenotyping two modifier mutants that differentially affect TOR signaling.
In Specific Aim 3, we plan to discover novel compound modifiers of TOR signaling that could be of greater therapeutic value for cardiomyopathy. At the end of the project, we expect to validate a cardioprotective function of TOR inhibition, to define autophagy as the major downstream signaling branch that confers this cardioprotective function, and to identify compounds that specifically interfere with the TOR-autophagy subpathway that might be of better therapeutic value than rapamycin. Our studies will establish adult zebrafish as a conservative animal model to identify novel modifiers of cardiomyopathy, as well as a complete in vivo model organism to facilitate drug discovery.
This proposal leverages the unique tools in zebrafish to seek TOR signaling-based therapies for cardiomyopathy and heart failure. We aim to use this unique animal model to identify gene modifiers of cardiomyopathy that will elucidate cardioprotective functions of TOR inhibition, and compounds in this pathway with therapeutic value for cardiomyopathy.
|Ma, Xiao; Ding, Yonghe; Wang, Yong et al. (2018) A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish. J Vis Exp :|
|Zhang, Hong; Dvornikov, Alexey V; Huttner, Inken G et al. (2018) A Langendorff-like system to quantify cardiac pump function in adult zebrafish. Dis Model Mech 11:|
|Dvornikov, Alexey V; de Tombe, Pieter P; Xu, Xiaolei (2018) Phenotyping cardiomyopathy in adult zebrafish. Prog Biophys Mol Biol 138:116-125|
|Lenning, Michael; Fortunato, Joseph; Le, Tai et al. (2017) Real-Time Monitoring and Analysis of Zebrafish Electrocardiogram with Anomaly Detection. Sensors (Basel) 18:|
|Ding, Yonghe; Long, Pamela A; Bos, J Martijn et al. (2017) A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene. JCI Insight 2:|
|Long, Pamela A; Theis, Jeanne L; Shih, Yu-Huan et al. (2017) Recessive TAF1A mutations reveal ribosomopathy in siblings with end-stage pediatric dilated cardiomyopathy. Hum Mol Genet 26:2874-2881|
|Wang, Lei; Ma, Xiao; Xu, Xiaolei et al. (2017) Systematic identification and characterization of cardiac long intergenic noncoding RNAs in zebrafish. Sci Rep 7:1250|
|Packard, René R Sevag; Baek, Kyung In; Beebe, Tyler et al. (2017) Automated Segmentation of Light-Sheet Fluorescent Imaging to Characterize Experimental Doxorubicin-Induced Cardiac Injury and Repair. Sci Rep 7:8603|
|Shih, Yu-Huan; Dvornikov, Alexey V; Zhu, Ping et al. (2016) Exon- and contraction-dependent functions of titin in sarcomere assembly. Development 143:4713-4722|
|Fei, Peng; Lee, Juhyun; Packard, René R Sevag et al. (2016) Cardiac Light-Sheet Fluorescent Microscopy for Multi-Scale and Rapid Imaging of Architecture and Function. Sci Rep 6:22489|
Showing the most recent 10 out of 28 publications