As described in the goals and objectives section of this report, this project consists of two specific aims: Study genes regulating vascular integrity We have used forward-genetic screens to identify new zebrafish mutants that disrupt cranial vascular integrity in the zebrafish, using exome sequencing and SNP analysis with a newly developed SNP database to perform higher-throughput cloning of mutants. These methods have led to the identification of the causative gene for approximately a third of the mutants thus far. We are currently further characterizing the molecular nature of the defects in these mutants, and continuing to identify the causative genetic defects in the other mutants. These new vascular integrity mutants promise to bring to light new pathways important in the maintenance of vascular barrier function. We are also studying the role of GDF6 (BMP13) in vascular integrity, demonstrating that this gene promotes maintenance of vascular integrity by suppressing excess VEGF signaling. Studying the acquisition and function of supporting vascular smooth muscle cells The vascular smooth cells (VSMC) that surround the endothelial tube play a critical role in regulating vascular tone and vascular integrity. We have recently begun examining the acquisition and function of these cells using the zebrafish. We have developed a number of useful transgenic tools to visualize and experimentally manipulate this cell population in the zebrafish, and are using these and other tools to, among other things, (i) examine the origins of these cells from early sclerotome, (ii) demonstrate that VSMC interaction with the endothelium us required to maintain the vascular basement membrane and restrict vessel diameter, (iii) elucidate the molecular pathways responsible for the selective acquisition of VSMC by arteries (as opposed to veins).

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U.S. National Inst/Child Hlth/Human Dev
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