This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Klippel-Trenaunay Syndrome (KTS) is a congenital vascular disease with associated cutaneous vascular malformations, vein varicosity, and overgrowth of affected limbs. Recent human genetic studies have implicated the VG5Q locus in the etiology of KTS. This work has suggested that VG5Q is a proangiogenic factor and that its overexpression in tissues of some KTS patients gives rise to the observed vascular differentiation defects. However, no lines of experimentation have been reported to define the in vivo activity of the VG5Q gene product or the mouse ortholog, Aggfl. In this work, gene expression and genetic analyses of Aggfl, the mouse ortholog of VG5Q, will beinitiated. Both loss-of-function and gain-of-function approaches will be used to define the activity of Aggfl in vivo. In the first Specific Aim, a detailed expression analysis of Aggfl will be completed, with a focus on tissues most affected in KTS. This work will define the sites of Aggfl activity in the mouse embryo and fetus, and will provide an important foundation for the remainder of proposal. In the second Specific Aim, a mutation analysis of the Aggfl locus will be performed. Mice harboring mutant alleles of Aggfl will be generated to understand the in vivo activity of Aggfl in the mouse. A focused analysis of the vasculature of mice and embryos lacking normal Aggfl function will be performed. This work will test the hypothesis that Aggfl is required for the endothelial differentiation of the embryonic and adult vasculature. In the third Specific Aim, an animal model for KTS will be generated and characterized. Transgenic mice will begenerated that overexpress Aggfl in the tissues of the developing embryonic vasculature.
This Aim will test the hypothesis that upregulated VG5Q activity is an underlying cause of the vascular defects in KTS. Completion of these studies will provide important animal models to further understand the etiology of KTS and the activity of an important gene implicated in this disease. Given our laboratory's expertise in mouse genetics and embryonic vascular development, we are well positioned to undertake the generation and characterization of these animal models. These reagents will form a foundation for further detailedstudies of the regulation of vascular differentiation and the genetic determinants of human congenital vascular malformations.
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