Integrating Environmental Cues at the Maternal-Fetal Vascular Interface

在母胎血管界面整合环境线索

• 批准号: 8676846
• 负责人: EMIN MALTEPE
• 金额: $ 38.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676846
• 关键词: Affect; Biochemical Genetics; Biology; Blood Circulation; Blood Vessels; Cell Culture Techniques; Cell Line; Cells; Cessation of life; Complex; Complication; Coronary Arteriosclerosis; Cues; Data; Defect; Development; Disease; Epigenetic Process; Etiology; Extracellular Matrix; Fetal Distress; Fetal Growth Retardation; Fetus; Functional disorder; Gene Expression; Gene Targeting; Genetically Engineered Mouse; Human; Hypertension; Hypoxia; Hypoxia Inducible Factor; In Vitro; Invaded; Investigation; Lead; Link; Maternal-Fetal Exchange; Mediating; Metabolic; Molecular; Morbidity - disease rate; Mus; Oxygen; Oxygen measurement, partial pressure, arterial; Pathogenesis; Pathway interactions; Pattern; Perfusion; Placenta; Placentation; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnant Women; Premature Birth; Premature Infant; Process; Pulmonary Hypertension; Renal Hypertension; Research; Resistance; Role; Seizures; Signal Pathway; Signal Transduction; Stem cells; Stress; Syndrome; System; Technology; Testing; Tissue Banking; Tissue Banks; Uterus; Vascular Diseases; Vascular remodeling; Vascularization; Woman; Work; cell fate specification; deprivation; design; fetal; fetus cell; in vitro Model; innovation; insight; mortality; next generation sequencing; novel; novel therapeutic intervention; pregnancy hypertension; premature; prevent; programs; response; stem cell differentiation; stem cell fate; stem cell niche; theories; trophoblast

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.

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，导致妇女的发病率和死亡率显着。其特征是胎儿胎盘细胞（滋养层）无法正确侵入并将母体血管重塑为低阻力导管，也可导致胎儿生长受限。由于胎盘的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解释其起源，因此仍然不可能预测或 防止。以前，我们的特点是在正常胎盘发育过程中的转录反应缺氧的关键作用。在这里，我们调查两个新的理论缺氧诱导因子（HIF），氧敏感的转录调节因子的作用，在病理状态下，损害胎盘血管化。首先，我们测试的假设，HIF可以诱导滋养层细胞的细胞外基质（ECM）的组成的变化。我们发现，改变滋养层干细胞（TSCs）培养的ECM通过与负责氧传感的通路交叉的通路触发分化依赖性HIF活化。因此，我们的初步观察表明，HIF可以整合在母胎界面的位置和代谢线索，以调节滋养层分化沿着，促进胎盘灌注。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浸润相关，因此我们的研究将有助于统一这些不同的调查线索。为了了解所涉及的机制，我们概述了一项研究计划，旨在确定连接氧气和ECM依赖性HIF激活和细胞命运决定在胎盘中的分子途径。第二，我们提供了令人信服的证据，一个典型的靶基因独立的作用，HIF在滋养层分化，大大改变了我们的观点，HIF生物学在发展过程中。我们建议利用转基因的TSC，下一代测序技术，和人类胎盘组织库来测试的假设，即非典型HIF-靶基因调节小鼠和人类胎盘，这一过程被破坏PE。重要的是，旨在解剖所涉及的途径的定向和无偏见的方法的组合可能会导致新的药理学靶点，以预防或治疗这种难治性疾病。