Hypertrophic cardiomyopathy in trabeculae-deficient zebrafish heart

Doctor's Name: 
Nicole Fleming
University of North Carolina, Chapel Hill

Collaboratively awarded through the CHF and AHA Congenital Heart Defect Research Awards

(Total Grant Amount $53,688; CHF portion = $16,583.15)

Congenital heart disease (CHD) is the leading cause of birth-related deaths in infants. Our research aims to understand what genetic or molecular factors are involved in regulating cardiac maladaptation when a critical event of heart development called cardiac trabeculation is disrupted. Trabeculae form in the ventricular wall and are vital for optimizing early heart function. Defective trabeculation is observed in various CHDs, and complete failure to form trabeculae causes embryonic lethality. Little is known about how trabeculation is regulated. Thus, it is extremely difficult to develop specific therapies for trabeculation defects in CHD patients. Therefore, this research aims to provide valuable information that can improve clinical outcomes of trabeculae defects in CHD patients.

Taking advantage of their optical clarity, external fertilization, rapid development and ease of manipulation, we will use zebrafish embryos to explore how vertebrate hearts compensate for a structural deficit. Specifically, we found that trabeculae-deficient erbb2 mutant ventricle develops a hypertrophic growth phenotype similar to that of an adult heart subjected to mechanical overload. In this proposal, we have designed experiments to identify the molecular signaling pathway(s) involved in this phenotype, which will ultimately lead us to a better understanding of the molecular basis of this congenital heart defect- associated hypertrophic cardiomyopathy.

Complete failure to form trabeculae is fatal and defective trabeculation is found in many congenital heart diseases. Our preliminary work has shown that hearts that lack trabeculae undergo hypertrophy (increase in size of heart cells) to help withstand increased workload on the heart. However, this process still eventually leads to heart failure. Interestingly, we have found that when a particular pathway is suppressed with pharmacological treatment, the function of the trabeculae-deficient heart is improved. Taken together, this work will facilitate the development of novel therapeutics to address trabeculation defects and can lend insight as to how other therapeutics might have adverse side affects on trabeculation.


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