The use of a biopolymer-fused form of VEGF-B for the treatment of Preeclampsia.

项目概要/摘要。 先兆子痫的临床特征是血压升高， 蛋白尿或其他症状在怀孕中期和晚期。在分子水平上， 已经表明，在治疗过程中，许多抗血管生成因子，如可溶性Flt-1（sFlt-1）， 这些女人的怀孕。这些因子的存在被认为与全身性内皮细胞损伤有关。 导致血压升高和其他母体综合征症状的功能障碍。 血管内皮生长因子（VEGF）蛋白质家族负责血管生成， 内皮细胞通过与包括Flt-1和Flk-1在内的一组受体相互作用发挥功能。sFlt-1，可溶性 Flt-1受体胞外结构域的形式在先兆子痫妇女的血液中上调， 作为VEGF陷阱发挥作用，阻止健康的VEGF信号传导至内皮细胞，并促进内皮细胞增殖。 功能障碍因此，用于中和增加的循环sFlt-1的治疗策略是用于治疗的主要候选者。 先兆子痫治疗以前在我的PI实验室的研究表明，VEGF-A的管理结合到一个 一种称为弹性蛋白样多肽（ELP）的载体蛋白在啮齿动物胎盘缺血模型中显著降低 游离s-Flt 1水平和正常化血压。ELP-VEGF-A蛋白可以结合并激活Flk-1， 它也可以通过隔离循环中的s-Flt-1发挥作用，s-Flt-1释放内源性VEGF-A 结合Flk-1受体并改善内皮功能。然而，VEGF-A管理具有许多 通过激活Flk-1受体介导的不良副作用。因此，新的治疗策略 我们实验室正在使用的是利用VEGF的其他同种型，包括VEGF-B，其结合sFlt-1，但不 直接激活Flk-1。本研究的目的是确定的药理学特性和疗效 ELP-VEGF-B治疗先兆子痫我们将使用已知的胎盘缺血模型， 作为子宫灌注压降低（RUPP）模型，它与许多表型相似， 先兆子痫的症状我们将检验用生物聚合物融合形式的VEGF治疗的假设， B将螯合sFlt-1和游离内源性VEGF-A，这将导致内皮功能的改善 和降低胎盘缺血模型中的血压。在目标1中，我们将确定体外活性 和ELP-VEGF-B的体内药代动力学、生物分布、胎盘转移和毒性特征， 静脉内和皮下给药。在目标2中，我们将确定ELP-VEGF-1的治疗功效。 B用于治疗先兆子痫的母体综合征。先兆子痫临床特征的改善 可能会延长发育中胎儿的妊娠期，并减轻疾病对胎儿的负担 母亲我们相信，通过探索使用不同的疗法治疗先兆子痫， 综合征，我们可以减少与疾病相关的后遗症，改善孕妇的结局， 子女

Project Summary/Abstract. Preeclampsia is clinically characterized by the development of elevated blood pressure combined with proteinuria or other symptoms during the second and third trimester of pregnancy. On the molecular level, it has been shown that there is an increase in a number of anti-angiogenic factors, such as soluble Flt-1 (sFlt-1), during pregnancy in these women. The presence of these factors is believed to be involved in the systemic endothelial dysfunction which contributes to the elevation in blood pressure and other symptoms of the maternal syndrome. The Vascular Endothelial Growth Factor (VEGF) family of proteins are responsible for angiogenesis and endothelial cell function via their interaction with a group of receptors including Flt-1 and Flk-1. sFlt-1, a soluble form of the extracellular domain of the Flt-1 receptor, is upregulated in the blood of preeclamptic women and functions as a VEGF trap, preventing healthy VEGF signaling to endothelial cells and contributing to endothelial dysfunction. Thus, therapeutic strategies to neutralize the increased circulating sFlt-1 are leading candidates for preeclampsia therapy. Previous studies in my PI’s lab have shown that administration of VEGF-A bound to a carrier protein called Elastin-like polypeptide (ELP) in a rodent model of placental ischemia significantly reduced free s-Flt1 levels and normalized blood pressure. The ELP-VEGF-A protein can bind and activate the Flk-1 receptor directly, and it can also function by sequestering circulating s-Flt-1, which frees endogenous VEGF-A to bind the Flk-1 receptor and improve endothelial function. However, VEGF-A administration has a host of adverse side effects mediated through its activation of the Flk-1 receptor. Therefore, the new therapeutic strategy being employed by our lab is to utilize other isoforms of VEGF, including VEGF-B, that bind to sFlt-1 but do not directly active Flk-1. The objective of this study is to determine the pharmacological properties and efficacy of ELP-VEGF-B for the treatment of preeclampsia. We will use an established model of placental ischemia known as the reduced uterine perfusion pressure (RUPP) model, which closely resembles many of the phenotypical features of preeclampsia. We will test the hypothesis that treatment with a biopolymer-fused form of VEGF- B will sequester sFlt-1 and free endogenous VEGF-A, which will result in improved endothelial function and reduced blood pressure in a model of placental ischemia. In Aim 1, we will determine the in vitro activity and in vivo pharmacokinetics, biodistribution, placental transfer, and toxicity profile of ELP-VEGF-B following intravenous and subcutaneous administration. In Aim 2, we will determine the therapeutic efficacy of ELP-VEGF- B for treatment of the maternal syndrome of preeclampsia. Improvements in the clinical features of preeclampsia may prove to increase the gestational period of developing fetuses and also lessen the burden of disease on the mother. We believe that by exploring the use of different therapeutics for the treatment of the preeclamptic syndrome, we can reduce the sequalae associated the disease and improve outcomes for pregnant women and their children.