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From zebrafish to humans: how TGF-β signaling shapes great vessel morphogenesis
Congenital heart defects (CHD) are among the most common birth defects, affecting about 1% of live births. Outflow tract (OFT) defects are the most populace of CHD cases annually.
From zebrafish to humans: how TGF-β signaling shapes great vessel morphogenesis
Mentor: Jennifer Schumacher, Ph.D.
Congenital heart defects (CHD) are among the most common birth defects, affecting about 1% of live births. Outflow tract (OFT) defects are the most populace of CHD cases annually. However, the etiology of OFT defects remains puzzling due to the complex cell and molecular interactions that guide heart development. Here, we report a novel zebrafish mutant we named pendulum (pen) with a malformed OFT and a defective adjacent bulboventricular valve. The pen mutant shows a positionally displaced ventral aorta (VA), the single vessel that connects the OFT to the pharyngeal arch arteries (PAA). Additionally, we found via RNA-Seq analysis that pen mutants have enhanced TGF-β signaling activity at 72 hours post fertilization (hpf) compared to its counterpart wild-type control siblings. The uniqueness of pen mutant makes it a suitable model to study the patterning of the great vessels (OFT/VA/PAA). As such, we aim to define the effect of hyperactivation of TGF-β signaling on the overall great vessel architecture. To tackle this goal, we devise a 2-step approach: (1) analyze the ventral aorta patterning, and (2) define the OFT/VA junction position relative to the PAA in pen mutants. Findings from this project will provide exciting insights into understanding how enhanced TGF-β signaling directs zebrafish OFT/VA/PAA patterning. This research will contribute to the broader discipline of developmental biology by revealing how TGF-β signaling impacts cardiac development, a critical step in understanding CHD and allowing for potential prevention or treatment. Understanding these mechanisms has direct implications for improving potential outcomes for individuals with CHD– a global plague. For my own personal development, this project will provide me with hands-on experience in developmental biology and scientific experimentation, and will deepen my understanding of the developmental mechanisms in human disease. As a first-generation student and aspiring physician, this experience will strengthen my ability to understand the clinical relevance behind research, which will allow me to foster the scientific inquiry necessary to be a successful physician.