KANSAS U COBRE: GENETIC MODELS OF CONGENITAL VASCULAR MALFORMATIONS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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VG 5 Q基因座与KTS的病因有关。这项工作表明，VG 5 Q是一种促血管生成因子，其在某些KTS患者的组织中的过表达引起了观察到的血管分化缺陷。然而，还没有报道定义VG 5 Q基因产物或小鼠直系同源物Aggf 1的体内活性的实验线。在这项工作中，Aggfl（VG 5 Q的小鼠直系同源物）的基因表达和遗传分析将被详细地描述。 启动。将使用功能丧失和功能获得方法来定义Aggfl的体内活性。在第一个具体目标中，将完成Aggfl的详细表达分析，重点关注KTS中受影响最大的组织。这项工作将确定小鼠胚胎和胎儿中Aggfl活性的位点，并将为提案的其余部分提供重要基础。在第二个特定目标中，将进行Aggfl基因座的突变分析。将产生携带Aggfl的突变等位基因的小鼠以了解Aggfl在小鼠中的体内活性。将对缺乏正常Aggfl功能的小鼠和胚胎的脉管系统进行集中分析。这项工作将测试这一假设，即Aggfl是胚胎和成人血管内皮分化所需的。在第三个特定目标中，将生成KTS的动物模型并进行表征。转基因小鼠将是 产生在发育中的胚胎脉管系统的组织中过表达Aggf 1的细胞。该目的将检验上调的VG 5 Q活性是KTS中血管缺陷的根本原因的假设。这些研究的完成将提供重要的动物模型，以进一步了解KTS的病因和与这种疾病有关的重要基因的活性。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，我们完全有能力进行这些动物模型的生成和表征。这些试剂将为进一步的详细研究奠定基础。 研究血管分化的调节和人类先天性血管畸形的遗传决定因素。

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.