Chemical Genetics of Vertebrate Vascular Development

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DESCRIPTION (provided by applicant): Understanding how the vertebrate circulatory system develops is a fundamental biological challenge with tremendous clinical implications. Molecular and genetic studies in zebrafish have highlighted the key roles of vascular endothelial growth factor (VEGF), Notch, and gridlock (grl) in the signaling pathway for embryonic vascular development. The zebrafish has proven to be remarkably amenable to chemical genetics analysis, in which small molecules discovered by high-throughput, phenotype-based screens are used as tools for dissecting cellular and developmental processes. Seminal work has recently identified a novel compound, GS4012, by virtue of its ability to suppress the vascular defect caused by a mutation in the grl gene. The grl suppressor screen has also identified another suppressor, GS4898, which has a completely different structure, and presumably distinct mechanism of action, from GS4012. This proposal takes molecular and chemical genetic approaches to study vertebrate vascular development, with three specific aims: 1) Determine how GS4012 rescues the gridlock vascular defect in mutant embryos. 2) Identify signaling pathways targeted by GS4012 in cultured endothelial cells. 3) Identify the mechanism of action of GS4898 in vivo and in vitro. This project will help to answer some of the outstanding questions regarding vasculogenesis and provide a valuable set of chemical tools for further study. Gridlock suppressors like GS4012 and GS4898, which modulate vascular development, may serve as lead compounds for treatments of important illnesses such ischemic vascular diseases. The candidate, who has a background in molecular biology and developmental genetics, has recently completed cardiology fellowship training. Dr. Hong now seeks to expand upon his scientific skills through unique resources available at the MGH's Cardiovascular Research Center. His two sponsors will guide him in chemical genetics, zebrafish biology, and cardiovascular cellular physiology, as well as in professional development. Dr. Hong's panel of advisors includes leaders in the fields of angiogenesis, zebrafish organogenesis, and zebrafish hemangioblast development. Mechanism of action studies of GS4012, GS4898, and additional gridlock suppressors will serve as a springboard for further scientific development, culminating in Dr. Hong's emergence as an independent investigator in the field of basic vascular biology.