VEGF signaling in placental development and disease

胎盘发育和疾病中的 VEGF 信号传导

基本信息

批准号：
9545830
负责人：
Nihar R Nayak
金额：
$ 32.02万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-16 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9545830
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 Stem cells 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 targeted treatment transcriptome treatment strategy trophoblast

项目摘要

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.

每年有超过 300,000 名女性死于妊娠并发症，还有超过 650 万人遭受痛苦导致终身残疾的并发症，为此花费了 410 亿美元的医疗费用。了解心脏细胞外绒滋养层细胞 (EVT) 的发育和分化我们的首要目标是制定基于机制的策略来解决大多数人类妊娠并发症的问题。预防、诊断和治疗与滋养层发育缺陷相关的妊娠并发症。有强有力的证据表明血管内皮生长因子（VEGF）直接作用于滋养层干细胞在交界区细胞和滋养层巨细胞特定亚型的分化中起关键作用小鼠中的 TGC 与人类的 EVT 是直系同源的，我们发现不同水平的蜕膜。植入部位的 VEGF 过度表达刺激胎盘产生有效的内源性 VEGF 拮抗剂可溶性 fms 样酪氨酸激酶 1 (sFlt1)，并在小鼠中诱导一系列类似于我们的初步数据表明，从先兆子痫到胎盘早剥等人类产科疾病。每种疾病的具体症状都与 TGC 子集的异常发育有关因此，我们捕获了胎盘早期 VEGF 过度表达的水平。发育对应于与不同的 TGC 相关的特定亚型的异常发育妊娠并发症以及与 sFlt1 产生过多相关的疾病可以通过以下方法治疗仅在妊娠后期减少 sFlt1 我们还发现存在不同的 EVT 亚型。过量的 VEGF 会导致人类特定 EVT 亚型不成比例地扩增。实验将确定 VEGF 在特定滋养层亚型发育中的作用（目标 1）， VEGF 水平在小鼠体内胎盘发育的各个阶段影响这些细胞，这些细胞如何细胞缺陷与特定妊娠结局相关（目标 2），以及 VEGF 信号传导的地点和时间途径可以作为预防和治疗策略的目标（目标 2）。用于解决这些问题，包括诱导胎盘和蜕膜特异性基因表达系统用于精确控制妊娠不同阶段的基因表达，以及纳米颗粒介导的递送最后，我们的初步数据表明类似的 EVT 可能是。人类胎盘中的 TGC 与小鼠的 TGC 存在相似的位置，并且 VEGF 可能在我们将使用激光表征人类胎盘中 EVT 的多样性。人绒毛膜滋养层祖细胞的显微解剖、整体转录谱和培养模型细胞分化（目标 3）。这些研究将描述之前未被认识到的细胞分化之间的关系。过度的 VEGF 信号传导和错误的滋养层分化以及由此产生的一系列妊娠疾病并为这些疾病的诊断和靶向治疗的开发提供具体指导。