ABSTRACT Heart failure remains the leading cause of morbidity and mortality in the US, afflicting nearly 5 million people. Recently, adult Zebrafish (Danio rerio) have been utilized to model different types of heart failure, and to search for genetic modifiers via mutagenesis screening. However, the small size of the zebrafish heart hinders precise electrical and mechanical assessments following genetic modifications. During the previous funding cycle, we integrated a flexible micro-electrode array with high-frequency ultrasonic transducers to demonstrate that early regenerating cardiomyocytes lack the electrical phenotypes needed to integrate into injured hearts. We further showed that the pressure gradient across the atrioventricular valve is greater than that across the ventriculobulbar valve following ventricular cryo-injury. However, the initial rise and subsequent normalization of ventricular passive (E) and active (A) filling waves (E/A ratios) indicate recovery of diastolic function. In the next funding cycle, we will combine our micro-sensing capacity with novel genetic models of cardiomyopathy to elucidate electromechanical coupling following chemotherapy-induced injury and genetic models of cardiomyopathy. Our multi-disciplinary team established an adult zebrafish model of doxorubicin (Dox)-induced cardiomyopathy (CM) as a conserved vertebrate model to investigate myocardial injury and regeneration in response to the breast cancer chemotherapy targeting ErbB2 (HER2)/NEU. Our team has further developed three murine genetic models of CM; namely, bag3 knockout (KO), mBAG3 overexpression (OE), and Imna KO. We have further developed a forward-genetic approach to identify genetic modifiers of Dox-induced CM. A pilot screen of >500 gene-breaking transposon (GBT) mutants has identified four GBT lines, of which GBT419/rxraa (retinoid X receptor alpha a) resembles mTOR to improve zebrafish survival following Dox-induced CM. Our goal is to integrate micro-sensors with advanced imaging to study electrical conduction and mechanical function of the injured myocardium in response to Dox-induced and 3 genetic models of CM. Our hypothesis is that genetic modifiers such as GBT419/rxraa promotes electromechanical coupling in Dox-induced and genetic models of CM to restore contractile function. To test our hypothesis, we have three aims: In Aim 1, we will determine electrical conduction in our Dox-induced and genetic models. In Aim 2, we will demonstrate mechanical function in our Dox-induced and genetic models. In Aim 3, we will assess electromechanical coupling following treatments with CM modifying genes. Overall, these aims will provide new insights into electromechanical coupling in cardiomyopathy using forward-genetics to discover therapeutic modifiers capable of restoring heart function.
|Effective start/end date||3/1/12 → 3/31/21|
- National Heart, Lung, and Blood Institute: $387,500.00
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