oa Think small: The zebrafish as a novel disease model in QCRC

Animal models are essential to understand the molecular and cellular basis of human pathologies. The zebrafish has gained significant attention as a novel model system and has several advantages over rodent models, including: (1) genetic and physiological similarity to humans, (2) a high fertility rate, (3) external fertilization, (4) ease of genetic manipulation, (5) enlarging library of heart-specific reporter genes, (6) ability to survive with a dysfunctional heart, (7) transparency enabling powerful imaging modalities. The zebrafish heart has only two chambers but beats with a heart rate comparable to humans. Several genetic models have been engineered, which successfully model cardiac conditions. Random integration of reporter genes by transposon-mediated transgenesis generated a large number of zebrafish lines, specifically labeling different cardiac cell types and tissues. These include marker genes that label the myocardium, epicardium, endocardium, the conduction system, and atrioventricular and aortic valves (see Figure). Such reporter lines are useful to monitor specific cardiac cell populations and to study their role in disease processes. Similar efforts have recently been employed to identify the cell population responsible for cardiac regeneration. Gene mutations identified in humans causing cardiomyopathies have been introduced in zebrafish and successfully modeled the disease process in this species. Moreover, chemical genetic approaches have been successfully employed to identify small molecules, which are able to reverse pathological conditions such as hypertrophic cardiomyopathy. These examples demonstrate the power and versatility of this model organism, which will pave the way for novel therapeutic opportunities to treat cardiovascular disease. In the Qatar Cardiovascular Research Center we plan to utilize the zebrafish model to study the genetic basis of aortic valve disease, hypertrophic cardiomyopathy, and heart failure. A zebrafish lab will be established in Doha as part of the network in order to develop local expertise and to contribute to the overall research efforts.