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.

Public Health Relevance

Heart failure remains the leading cause of morbidity and mortality in the US, afflicting nearly 5 million people. Discovering novel genetic modifiers to achieve therapeutic effects for heart failure is highly relevant to public health. For this reason, our goal is to integrate our precision technologies with genetic models of heart failure to provide new insights into cardiac electrical and mechanical integration to discover therapeutic modifiers capable of restoring heart function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111437-07
Application #
9676310
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Adhikari, Bishow B
Project Start
2012-03-01
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Ding, Yichen; Ma, Jianguo; Langenbacher, Adam D et al. (2018) Multiscale light-sheet for rapid imaging of cardiopulmonary system. JCI Insight 3:
Baek, Kyung In; Li, Rongsong; Jen, Nelson et al. (2018) Flow-Responsive Vascular Endothelial Growth Factor Receptor-Protein Kinase C Isoform Epsilon Signaling Mediates Glycolytic Metabolites for Vascular Repair. Antioxid Redox Signal 28:31-43
Luo, Yuan; Abiri, Parinaz; Zhang, Shell et al. (2018) Non-Invasive Electrical Impedance Tomography for Multi-Scale Detection of Liver Fat Content. Theranostics 8:1636-1647
Baek, Kyung In; Packard, René R Sevag; Hsu, Jeffrey J et al. (2018) Ultrafine Particle Exposure Reveals the Importance of FOXO1/Notch Activation Complex for Vascular Regeneration. Antioxid Redox Signal 28:1209-1223
Abiri, Arash; Ding, Yichen; Abiri, Parinaz et al. (2018) Simulating Developmental Cardiac Morphology in Virtual Reality Using a Deformable Image Registration Approach. Ann Biomed Eng 46:2177-2188
Ding, Yichen; Lee, Juhyun; Hsu, Jeffrey J et al. (2018) Light-Sheet Imaging to Elucidate Cardiovascular Injury and Repair. Curr Cardiol Rep 20:35
Ding, Yichen; Bailey, Zachary; Messerschmidt, Victoria et al. (2018) Light-sheet Fluorescence Microscopy for the Study of the Murine Heart. J Vis Exp :
Baek, Kyung In; Ding, Yichen; Chang, Chih-Chiang et al. (2018) Advanced microscopy to elucidate cardiovascular injury and regeneration: 4D light-sheet imaging. Prog Biophys Mol Biol 138:105-115
Lee, Juhyun; Chou, Tzu-Chieh; Kang, Dongyang et al. (2017) A Rapid Capillary-Pressure Driven Micro-Channel to Demonstrate Newtonian Fluid Behavior of Zebrafish Blood at High Shear Rates. Sci Rep 7:1980
Ding, Yichen; Lee, Juhyun; Ma, Jianguo et al. (2017) Light-sheet fluorescence imaging to localize cardiac lineage and protein distribution. Sci Rep 7:42209

Showing the most recent 10 out of 37 publications