Integrating Environmental Cues at the Maternal-Fetal Vascular Interface

描述（由申请人提供）：妊娠高血压或先兆子痫 (PE) 是一种复杂的血管疾病，会导致女性显着发病和死亡。其特点是胎儿胎盘细胞（滋养层）无法正确侵入母体血管并将其重塑为低阻力管道，它也可能导致胎儿生长受限。由于胎盘分娩是唯一确定的治疗方法，因此它是早产的主要原因。由于没有统一的理论可以解释其起源，因此仍然无法预测或 防止。之前，我们描述了正常胎盘发育过程中缺氧转录反应的关键作用。在这里，我们研究了关于缺氧诱导因子（HIF）（一种氧敏感转录调节因子）在损害胎盘血管化的病理状态下的作用的两个新理论。首先，我们测试了以下假设：HIF 可以通过改变细胞外基质 (ECM) 的组成在滋养细胞中诱导。我们发现，改变培养滋养层干细胞 (TSC) 的 ECM 会通过与负责氧传感的途径相交叉的途径触发分化依赖性 HIF 激活。因此，我们的初步观察表明，HIF 可以整合母胎界面的位置和代谢线索，沿着促进胎盘灌注的路线调节滋养层分化。由于氧输送受损和 ECM 重塑通常与 PE 中滋养层分化受损和血管内侵袭相关，因此我们的研究将有助于统一这些不同的探究线索。为了了解所涉及的机制，我们概述了一项研究计划，旨在确定胎盘中连接氧气和 ECM 依赖性 HIF 激活以及细胞命运决定的分子途径。其次，我们为 HIF 在滋养层分化过程中的典型靶基因独立作用提供了令人信服的证据，极大地改变了我们对发育过程中 HIF 生物学的看法。我们建议利用转基因 TSC、下一代测序技术和人类胎盘组织库来检验以下假设：非典型 HIF 靶基因调节小鼠和人类胎盘，并且这一过程在 PE 中被破坏。重要的是，旨在剖析所涉及途径的定向和公正方法的结合可能会产生新的药理学靶点来预防或治疗这种棘手的疾病。

DESCRIPTION (provided by applicant): Pregnancy-induced hypertension, or preeclampsia (PE), is a complex vascular disorder that causes significant morbidity and mortality in women. Characterized by an inability of fetal placental cells (trophoblasts) to properly invade and remodel maternal blood vessels into low resistance conduits, it can also result in fetal growth restriction. Since delivery of the placenta is the only definitive cure, it is a leading cause of preterm birth. Because no unifying theory explains its origins, it remains impossible to predict or prevent. Previously, we characterized the critical role of the transcriptional response to oxygen deprivation during normal placental development. Here, we investigate two novel theories regarding the role of Hypoxia-inducible Factor (HIF), an oxygen sensitive transcriptional regulator, during pathological states that compromise placental vascularization. First, we test the hypothesis that HIF can be induced in trophoblasts by changes in the composition of the their extracellular matrix (ECM). We show that altering the ECM upon which trophoblast stem cells (TSCs) are cultured triggers differentiation-dependent HIF activation via pathways that intersect with those responsible for oxygen sensing. Our preliminary observations therefore suggest that HIF can integrate positional and metabolic cues at the maternal-fetal interface to regulate trophoblast differentiation along lines that promote placental perfusion. As compromised oxygen delivery and ECM remodeling are frequently associated with impaired trophoblast differentiation and endovascular invasion in the setting of PE, our studies will help unify these disparate threads of inquiry. To understand the mechanisms involved, we outline a research program designed to identify the molecular pathways linking oxygen and ECM-dependent HIF activation and cell fate determination in the placenta. Second, we provide compelling evidence for a canonical target gene independent role for HIF during trophoblast differentiation, dramatically altering our view of HIF biology during development. We propose to utilize genetically modified TSCs, next generation sequencing technologies, and a human placenta tissue bank to test the hypothesis that atypical HIF-target genes regulate mouse and human placentation, and that this process is disrupted in PE. Importantly, the combination of directed and unbiased approaches designed to dissect the pathways involved may lead to novel pharmacological targets to prevent or treat this intractable disorder.