Integrating Environmental Cues at the Maternal-Fetal Vascular Interface

描述(申请人提供)：妊娠高血压综合征，或先兆子痫(PE)，是一种复杂的血管疾病，在妇女中导致显著的发病率和死亡率。以胎儿胎盘细胞(滋养层细胞)无法正确侵入母体血管并将其重塑为低阻力管道为特征，也可导致胎儿生长受限。由于胎盘的分娩是唯一有效的治疗方法，它也是导致早产的主要原因。因为没有统一的理论来解释它的起源，所以仍然不可能预测或 预防。在此之前，我们描述了在正常胎盘发育过程中，对缺氧的转录反应的关键作用。在这里，我们研究了两种新的理论，即缺氧诱导因子(HIF)，一种氧敏感的转录调节因子，在损害胎盘血管形成的病理状态中的作用。首先，我们验证了滋养层细胞外基质(ECM)组成的改变可以诱导滋养层细胞HIF的假设。我们发现，改变滋养层干细胞(TSCs)培养所在的ECM，可以通过与负责氧气感应的通路相交的途径，触发依赖分化的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信号，以调节滋养层细胞的分化，从而促进胎盘的灌流。由于在PE环境中，氧输送受损和ECM重塑经常与滋养细胞分化受损和血管内侵袭有关，我们的研究将有助于统一这些不同的研究线索。为了了解相关机制，我们概述了一项研究计划，旨在确定胎盘中氧和细胞外基质依赖的HIF激活和细胞命运决定之间的分子通路。第二，我们提供了令人信服的证据，证明了HIF在滋养层分化过程中具有典型的靶基因独立作用，极大地改变了我们对HIF生物学发育过程的看法。我们建议利用转基因的TSCs、下一代测序技术和人类胎盘组织库来测试非典型HIF靶基因调控小鼠和人类胎盘形成的假设，并且这一过程在PE中被破坏。重要的是，旨在剖析所涉及的途径的定向和无偏见方法的组合可能会导致预防或治疗这种顽固性疾病的新的药理靶点。

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.