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. We have already characterized the role of GDF6 (BMP13) in vascular integrity, demonstrating that this gene promotes maintenance of vascular integrity by suppressing excess VEGF signaling. We are currently 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. 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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| Krispin, Shlomo; Stratman, Amber N; Melick, Chase H et al. (2018) Growth Differentiation Factor 6 Promotes Vascular Stability by Restraining Vascular Endothelial Growth Factor Signaling. Arterioscler Thromb Vasc Biol 38:353-362 |
| Stratman, Amber N; Pezoa, Sofia A; Farrelly, Olivia M et al. (2017) Interactions between mural cells and endothelial cells stabilize the developing zebrafish dorsal aorta. Development 144:115-127 |
| Stainier, Didier Y R; Raz, Erez; Lawson, Nathan D et al. (2017) Guidelines for morpholino use in zebrafish. PLoS Genet 13:e1007000 |
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| Ulrich, Florian; Carretero-Ortega, Jorge; Menéndez, Javier et al. (2016) Reck enables cerebrovascular development by promoting canonical Wnt signaling. Development 143:1055 |
| Kallakuri, Sowjanya; Yu, Jianxin A; Li, Jade et al. (2015) Endothelial cilia are essential for developmental vascular integrity in zebrafish. J Am Soc Nephrol 26:864-75 |
| Miskinyte, Snaigune; Butler, Matthew G; Herve, Dominique et al. (2011) Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya. Am J Hum Genet 88:718-28 |
| Butler, Matthew G; Gore, Aniket V; Weinstein, Brant M (2011) Zebrafish as a model for hemorrhagic stroke. Methods Cell Biol 105:137-61 |
| Fujita, Misato; Cha, Young R; Pham, Van N et al. (2011) Assembly and patterning of the vascular network of the vertebrate hindbrain. Development 138:1705-15 |
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