KANSAS U COBRE: GENETIC MODELS OF CONGENITAL VASCULAR MALFORMATIONS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Klippel-Trenaunay综合征(KTS)是一种先天性血管疾病，伴有皮肤血管畸形、静脉曲张和患肢过度生长。最近的人类遗传学研究表明，VG5Q基因座与KTS的病因有关。本工作提示VG5Q是一种促血管生成因子，其在某些KTS患者组织中的过度表达导致了观察到的血管分化缺陷。然而，目前还没有关于VG5Q基因产物或小鼠同源基因Aggf1在体内活性的实验报道。在这项工作中，VG5Q的小鼠同源基因Aggf1的基因表达和遗传分析将被 已启动。功能丧失和功能获得两种方法将被用来确定Aggf1在体内的活性。在第一个具体目标中，将完成Aggf1的详细表达分析，重点是在KTS中受影响最严重的组织。这项工作将确定Aggf1在小鼠胚胎和胎儿中的活性部位，并将为后面的提议提供重要的基础。在第二个特定目标中，将进行Aggf1基因座的突变分析。将产生携带Aggf1突变等位基因的小鼠，以了解Aggf1在小鼠体内的活性。将对缺乏正常AggFL功能的小鼠和胚胎的血管系统进行重点分析。这项工作将检验这一假设，即Aggf1是胚胎和成人血管系统内皮细胞分化所必需的。在第三个具体目标中，将建立KTS的动物模型并进行表征。转基因小鼠将成为 在发育中的胚胎血管系统的组织中过度表达Aggf1。这一目标将检验VG5Q活性上调是KTS血管缺陷的潜在原因的假设。这些研究的完成将为进一步了解KTS的病因和与该疾病有关的重要基因的活性提供重要的动物模型。鉴于我们实验室在小鼠遗传学和胚胎血管发育方面的专业知识，我们有能力承担这些动物模型的生成和表征。这些试剂将为进一步的详细分析奠定基础 人类先天性血管畸形血管分化调控及遗传决定因素的研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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 be initiated. 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 be generated 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 detailed studies of the regulation of vascular differentiation and the genetic determinants of human congenital vascular malformations.