Exciting advances in the fields of chemistry, diversity-oriented synthesis, and high-throughput screening have resulted in powerful new chemical approaches for the study of biological processes. Small molecules discovered by high-throughput, phenotype-based screening have become valuable tools for dissecting biological pathways, particularly in the area of cell biology, and are leading to the development of novel therapies for human diseases. The small size and transparency of the zebrafish embryo have made it a remarkably useful model organism for performing phenotype-based genetic screens. By combining chemical screening technologies with the strengths of the zebrafish, new chemical tools for dissecting organismal processes (such as ontogeny) can be developed. This proposal seeks to use a zebrafish-based chemical screening approach to identify the mechanisms by which arterial and venous fates are established during development. These studies will help answer the many fundamental questions that remain about how arterial and venous progenitors arise, reach their target tissues, and make appropriate connections with each other. In addition, chemical tools for manipulating these processes may provide new options for treatment of diseases that hinge upon the formation of new blood vessels (such as cancer, trauma, myocardial infarction, and stroke). Specifically, the aims are: 1). To identify small molecule modifiers of an existing mutation that models a human vascular disease. 2). To identify small molecules that alter establishment of vessel identity during normal development. 3). To determine the biological pathways and molecular targets of small molecules with vascular activity. This project benefits from the relevant expertise of the key personnel and a unique group of collaborators. The project will provide the zebrafish community with a valuable set of chemical tools for studying vasculogenesis. Moreover, it will establish novel methodologies for phenotype-based chemical screening that complement traditional genetic screens and can be applied broadly to other areas of zebrafish research.
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