Exosome Based Placental Maternal Communication

基于外泌体的胎盘母体通讯

• 批准号: 10514817
• 负责人: Yoel Sadovsky
• 金额: $ 41.57万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514817
• 关键词: Adult; Affect; Allografting; Apoptotic; Attenuated; Biological; Biological Process; Biopsy; Blood; Blood Cells; Blood Circulation; Bulla; Cell Line; Cell membrane; Cell physiology; Cells; Chromosome 19; Clinical; Communication; Conflict (Psychology); Cytomegalovirus; DNA Viruses; Data; Diagnostic; Dimensions; Disease; Distant; Endocrine; Environment; Equilibrium; Excision; Exhibits; Fetal Development; Fetal Growth Retardation; Fetal Tissues; Fetus; Functional disorder; Gases; Genomics; Glycoproteins; Growth Factor; HIV; Health; Hormones; Human; Immune signaling; Immunologics; Infection; Injury; Investigation; Knowledge; Lead; Maternal Physiology; Mediating; Metabolic; MicroRNAs; Modeling; Mothers; Mus; Nutrient; Organ; Organism; Pathway interactions; Physiological; Physiological Adaptation; Placenta; Placental Biology; Plasma; Play; Positioning Attribute; Pre-Eclampsia; Predisposition; Pregnancy; Pregnant Women; Premature Birth; Process; Proteins; Proteomics; RNA Viruses; Regulation; Research; Resistance; Role; Rubella; Signal Transduction; Simplexvirus; Steroids; Termination of pregnancy; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Transgenic Mice; Vesicle; Viral; Virus Diseases; Waste Products; Work; base; cell type; design; engineered exosomes; exosome; experimental study; fetal; human pathogen; in vivo; interest; lipidomics; microvesicles; migration; nano; nanoparticle; nanoscale; nanosensors; nanovesicle; novel; paracrine; peptide hormone; pregnancy disorder; pregnancy health; premature; prevent; resilience; steroid hormone; trafficking; trophoblast; uptake; viral resistance

PROJECT SUMMARY/ABSTRACT Pregnancy is a unique period in which the inherent biological complexity of any single human organism is exponentially amplified by an intimate interaction between a rapidly developing fetus and an adult mother who exhibits remarkable physiological adaptations over the nine months of pregnancy. Importantly, the biological interests of the two organisms are not always congruent, reflecting conflicting metabolic interests and limited supplies. Furthermore, maternal-fetal interaction does not occur through a passive sieve, but is actively and dynamically orchestrated by the placenta, an organ with its own set of physiological needs. It is therefore apparent that any disruption of the homeostatic equilibrium among the mother, placenta, fetus or their environment may manifest as a clinical disease that challenges maternal physiology (e.g., preeclampsia) or fetal development (e.g., fetal growth restriction), or may lead to premature termination of the pregnancy (e.g., preterm birth). The intact function of the placenta includes a set of signals that are generated by placental trophoblasts and communicated to the maternal and/or the fetal compartments. These signals include hormones (proteins, glycoproteins, steroid hormones) and growth factors, which have a paracrine and endocrine effect on maternal and, possibly, fetal tissues. Our new line of research centers on nanovesicle (exosome)-based communication. These exosomes are produced in human trophoblasts and harbor signals that are germane to pregnancy health. Among these signals are placenta-specific microRNAs (miRNAs) that, we recently showed, confer viral resistance to recipient cells. These miRNAs may also impact local placental biological processes, such as trophoblast migration and invasion. While the placenta produces an abundant number of exosomes, their target tissues are currently unknown. Moreover, the mechanisms by which placental exosomes deliver their cargo to target cells and the regulation of their intracellular function have not been hitherto investigated. We therefore seek to test the hypothesis that human trophoblastic exosomes use specific uptake mechanisms to target maternal tissues, locally and distantly, and impact cell function. We will test our hypothesis using human trophoblasts and exosomes derived from pregnant women. For those experiments that cannot be performed in humans, we will use mice that have been validated as appropriately modeling the human processes under study. Ultimately, our data will illuminate previously unknown mechanisms of crucial, exosome-based communication between the feto-placental and maternal compartments. Further, as placental exosomes are accessible via the blood, data generated by our investigation will introduce new means to investigate the human placenta, and may promote the use of exosomes as part of the diagnostics of placental dysfunction and indicate new avenues for nanoparticle-based therapeutics.

项目概要/摘要 怀孕是一个独特的时期，在这个时期，任何单个人类有机体固有的生物复杂性都受到影响。 快速发育的胎儿和成年母亲之间的亲密互动会呈指数级放大。 在怀孕九个月期间表现出显着的生理适应。重要的是，生物 两种生物体的利益并不总是一致的，反映了代谢利益的冲突和有限的 补给品。此外，母婴互动不是通过被动的筛子发生的，而是主动、主动的。 由胎盘动态地协调，胎盘是一个有自己的生理需求的器官。因此是 显然，任何对母亲、胎盘、胎儿或其母体之间稳态平衡的破坏 环境可能表现为挑战母体生理的临床疾病（例如先兆子痫）或 胎儿发育（例如，胎儿生长受限），或可能导致妊娠提前终止（例如， 早产）。胎盘的完整功能包括胎盘产生的一组信号 滋养层并与母体和/或胎儿区室连通。这些信号包括 激素（蛋白质、糖蛋白、类固醇激素）和生长因子，具有旁分泌和 对母体组织和可能对胎儿组织的内分泌影响。我们的新研究线以纳米囊泡为中心 基于（外泌体）的通讯。这些外泌体是在人类滋养层细胞中产生并包含信号 这与怀孕健康密切相关。这些信号包括胎盘特异性 microRNA (miRNA)， 我们最近表明，赋予受体细胞病毒抵抗力。这些 miRNA 也可能影响局部胎盘 生物过程，例如滋养层迁移和侵袭。虽然胎盘产生丰富的 外泌体的数量，其靶组织目前未知。此外，其机制 胎盘外泌体将其货物递送至靶细胞，并且其细胞内功能的调节尚未实现 迄今已被调查。因此，我们试图检验人类滋养层外泌体使用的假设 局部和远处针对母体组织的特定摄取机制，并影响细胞功能。我们将 使用人类滋养层和来自孕妇的外泌体来检验我们的假设。对于那些 对于无法在人类身上进行的实验，我们将使用经过适当验证的小鼠 对所研究的人类过程进行建模。最终，我们的数据将阐明以前未知的问题 胎儿胎盘和母体之间基于外泌体的重要通讯机制 隔间。此外，由于胎盘外泌体可以通过血液获取，因此我们生成的数据 调查将引入研究人类胎盘的新手段，并可能促进使用 外泌体作为胎盘功能障碍诊断的一部分，并表明基于纳米颗粒的新途径 疗法。