VEGF signaling in placental development and disease

胎盘发育和疾病中的 VEGF 信号传导

• 批准号: 10190619
• 负责人: Nihar R Nayak
• 金额: $ 27.86万
• 依托单位: UNIVERSITY OF MISSOURI KANSAS CITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190619
• 关键词: Abruptio Placentae; Acute; Address; Affect; Blood flow; Cell Differentiation process; Cell physiology; Cells; Chorion; Clinical; Data; Decidua; Defect; Development; Diagnosis; Diagnostic; Discipline of obstetrics; Disease; Endothelial Growth Factors Receptor; Fetal health; Functional disorder; Gene Expression; Giant Cells; Goals; Growth Factor Overexpression; Health; Health Care Costs; Heart; Hemorrhage; Heterogeneity; Human; Hypoxia; Intercellular Junctions; Knowledge; Lasers; Lead; Life; Location; Maternal Health; Mediating; Microdissection; Modality; Molecular; Mus; Pathogenesis; Pathologic; Pathology; Placenta; Placenta Diseases; Placentation; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Prevention; Process; Production; Research; Risk; Role; Signal Pathway; Signal Transduction; Site; Spiral Artery of the Endometrium; Symptoms; System; Techniques; Therapeutic; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Woman; Work; angiogenesis; base; disability; disorder subtype; experimental study; human model; implantation; improved; in vivo; insight; knock-down; nanoparticle; novel; novel diagnostics; novel therapeutics; precursor cell; pregnancy disorder; prevent; response; stem cells; targeted treatment; transcriptome; treatment strategy; trophoblast

Every year over 300,000 women die from pregnancy complications, and over 6.5 million more suffer complications that result in life-long disability, for which $41 billion is spent on healthcare costs. However, little is known about the development and differentiation of the cells—extravillous trophoblasts (EVTs)—at the heart of most human pregnancy complications. Our overarching goal is to develop mechanism-based strategies to prevent, diagnose, and treat pregnancy complications associated with faulty trophoblast development. We have strong evidence that vascular endothelial growth factor (VEGF) acts directly on trophoblast stem cells and plays a key role in the differentiation of junctional zone cells and specific subtypes of trophoblast giant cells (TGCs) in mice, which are orthologous to EVTs in humans. We discovered that different levels of decidual VEGF overexpression at the implantation site stimulates placental production of the potent endogenous VEGF antagonist soluble fms-like tyrosine kinase 1 (sFlt1) and induces a spectrum of symptoms in mice similar to those of human obstetrical diseases, from preeclampsia to abruptio placentae. Our preliminary data show that specific symptoms of each of those diseases are associated with abnormal development of a subset of TGCs and junctional zone cells. Thus, we hypothesize that the level of VEGF overexpression during early placental development corresponds to abnormal development of specific subtypes of TGCs associated with distinct pregnancy complications and that the diseases associated with excess sFlt1 production can be treated by reducing sFlt1 only at later stages of pregnancy. We also hypothesize that different EVT subtypes exist and that excess VEGF can cause disproportionate expansion of specific EVT subtypes in humans. Thus, our experiments will define the role of VEGF in the development of specific trophoblast subtypes (Aim 1), how levels of VEGF affect these cells at each stage of placental development in vivo in the mouse, how these cellular defects are related to specific pregnancy outcomes (Aim 2), and where and when VEGF signaling pathways can be targeted for prevention and therapeutic strategies (Aim 2). Several novel techniques will be used to address these questions, including inducible placenta- and decidua-specific gene expression systems for precise control of gene expression at discrete stages of pregnancy, and nanoparticle-mediated delivery of morpholinos to specific cells in the placenta. Finally, our preliminary data suggest that analogous EVTs may be present at similar locations in the human placenta as TGCs in mice and that VEGF may play a similar role in human trophoblast differentiation. We will characterize the diversity of EVTs in human placenta using laser microdissection, global transcriptional profiling, and a culture model of human chorionic trophoblast progenitor cell differentiation (Aim 3). These studies will characterize the previously unappreciated relationship between excess VEGF signaling and faulty trophoblast differentiation and the resulting spectrum of pregnancy disorders and provide specific guidance for the development of diagnostics and targeted therapies for these disorders.

每年超过30万名妇女死于怀孕并发症，超过650万的妇女受苦 导致终身残疾的并发症，为此，410亿美元用于医疗保健费用。但是，很少 关于细胞的发展和分化（Extraville滋养细胞（EVT））已知 大多数人类怀孕并发症。我们的总体目标是制定基于机制的策略 预防，诊断和治疗与滋养细胞发育不良有关的妊娠并发症。我们 有强有力的证据表明血管内皮生长因子（VEGF）直接在滋养细胞上作用 并在分化连接区细胞和滋养细胞巨人的特定亚型中起关键作用 小鼠中的细胞（TGC），与人类的EVT直源。我们发现不同层次 植入部位的VEGF过表达刺激有效的内源性VEGF的斑点产生 拮抗剂固体FMS样酪氨酸激酶1（SFLT1），并在类似的小鼠中诱导一系列符号 从先兆子痫到突破性遗迹的人类产科疾病。我们的初步数据表明 每种疾病的特定症状都与TGC子集的异常发育有关 和连接区细胞。这就是我们假设早期植物的VEGF过表达水平 发展对应于与不同的TGC的特定亚型的异常发展 怀孕并发症以及与过量SFLT1产生相关的疾病可以治疗 仅在怀孕的后期才减少SFLT1。我们还假设存在不同的EVT亚型，并且 超过VEGF会导致人类特定EVT亚型的不成比例扩张。那，我们的 实验将定义VEGF在特定滋养细胞亚型发展中的作用（AIM 1），如何 VEGF的水平在小鼠体内的斑点发育的每个阶段都会影响这些细胞，这些细胞如何 细胞缺陷与特定的妊娠结局有关（AIM 2）以及在何时何地vegf信号传导 可以将途径用于预防和治疗策略（AIM 2）。几种新颖的技术将是 用于解决这些问题，包括可诱导的plabeta-和decidua特异性基因表达系统 为了精确控制妊娠离散阶段的基因表达，以及纳米颗粒介导的递送 形态学到多余的特定细胞。最后，我们的初步数据表明类似的EVT可能是 在人类斑点的类似位置与小鼠中的TGC相似，而VEGF可能在 人滋养细胞的分化。我们将使用激光表征人斑ta中EVT的多样性 微分解，全局转录分析和人绒毛膜滋养细胞祖细胞的培养模型 细胞分化（目标3）。这些研究将表征先前未欣赏的关系 过多的VEGF信号传导和滋养细胞分化错误以及妊娠疾病的范围 并为开发这些疾病的诊断和靶向疗法提供具体的指导。