Despite current treatment regimens, heart failure remains the leading cause of morbidity and mortality in the US and developed world due to failure to adequately replace lost ventricular myocardium from ischemia- induced infarct. Adult mammalian ventricular cardiomyocytes have a limited capacity to divide, and this proliferation is insufficient to overcome the significant loss of myocardium from ventricular injury. However, zebrafish (Danio rerio) possess the remarkable capacity to regenerate a significant amount of myocardium in injured hearts, and thus, represent an emerging vertebrate model for regenerative medicine and cardiovascular research. While the small size of zebrafish system allows for high-throughput research, the small heart size (1-2 mm in length) renders it challenging to perform functional physiological analyses. Toward this end, our collaborated efforts have enabled the applications of the micro-electrical cardiogram (ECG) and high-frequency ultrasonic transducers (>45 MHz) to further investigate the electrical and mechanical attributes of regenerating myocardium in injured zebrafish hearts. We have observed that ventricular repolarization (ST intervals and T waves) failed to normalize despite fully regenerated myocardium at 60 days post ventricular amputation, suggesting further cardiac remodeling may be required to fully integrate regenerating myocardium with host myocardium. We hypothesize that early regenerating cardiomyocytes may lack the electrical and mechanical cardiac phenotypes, and thus may require additional cardiac cellular remodeling for full electrical and mechanical integration into injured hearts. To assess the restoration of cardiac function during cardiac regeneration, we propose to interface implantable flexible micro-electrode arrays with high- frequency ultrasonic transducers and optical voltage mapping to test the conduction and mechanical phenotypes, followed by mechanistic assessment by conditionally blocking or activating Wnt/2-catenin and FGF signaling pathways. The development and application of implantable and flexible micro-electrode arrays, high frequency ultrasonic transducers hold a great promise in the era of stem cell and regenerative medicine. In sum, our concerted efforts will likely provide both novel technology and new mechanistic insights into cardiac conduction and mechanical phenotypes in response to genetic, epigenetic, and pharmaceutical perturbations with relevance to regenerative medicine.

Public Health Relevance

In the era of stem cell and regenerative medicine, there is a considerable interest to assess the phenotypes of injured and early regenerated cardiomyocytes. The advent of Micro-electro-mechanical systems (MEMS) sensors has enabled us to measure conduction and mechanical phenotypes of injured and regenerating hearts with both high spatial and temporal resolution in the small animal system. Thus, our goal is to test the hypothesis that regenerating myocardium may require additional cardiac cellular remodeling for full electrical and mechanical integration into injured hearts.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111437-04
Application #
8847368
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Adhikari, Bishow B
Project Start
2012-03-01
Project End
2016-02-29
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
4
Fiscal Year
2015
Total Cost
$371,349
Indirect Cost
$41,983
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
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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
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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

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