10.17615/jqb5-n082

MOLECULAR REGULATION OF CARDIOVASCULAR DEVELOPMENT AND DISEASE

Abstract

Congenital heart disease (CHD) represents the most common type of human birth defect, accounting for approximately one-third of all major congenital abnormalities. These structural anomalies primarily arise due to genetic and transcriptional dysregulations during early development and maturation of the heart. Severe CHDs can lessen a patient’s quality of life or lead to various life-threatening diseases like heart failure and even death. Given that CHDs can also give rise to adult cardiomyopathies, it is necessary to have a better understanding of the etiologies and the molecular regulation of factors involved in normal cardiac development and disease. The process from cardiogenesis to the formation of a mature and fully functional heart requires precise coordination of transcription factors, signaling molecules, and epigenetic components. In these studies, we utilized the zebrafish for its optical transparency, its ease of pharmacological and genetic manipulation, and its simplistic yet complex circulatory system to investigate the molecular basis of events that lead to defective hearts during early and late embryogenesis. A myriad of studies has shown the importance of several transcriptional and epigenetic factors in proper cardiogenesis, as mutations in cardiac-specific genes lead to heart defects that resemble those observed in human CHD patients. Furthermore, previous evidence indicates that as the heart matures, appropriate expansion and remodeling of the chambers are necessary to prevent poor contraction, increased hemodynamic burden, and compromised homeostasis. In Chapter 2, trabeculae-deficient erbb2 zebrafish mutants were used to evaluate the function of trabeculae, luminal muscular protrusions within the heart, during chamber maturation. The data revealed that trabeculae function to possibly relieve the heart of mechanical-pressure overload, as absence of trabecular formation led to pathological hypertrophy and decreased cardiac function. Chapter 3 explores the events of early heart development in zebrafish embryos that lack Ring1b, an epigenetic factor belonging to the Polycomb Repressive Complex 1. Data highlighted the requirement of Ring1b in SHF-mediated development, which has not been explored in zebrafish or mice. Overall, these studies provide new insights into the cellular, molecular, and functional regulation of distinct steps during cardiac development: SHF-mediated expansion and chamber maturation.Doctor of Philosoph

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