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.

项目摘要/摘要 怀孕是一个独特的时期 迅速发展 在怀孕的九个月中，表现出显着的生理适应。重要的是，生物学 这两个生物的利益并不总是一致的，反映了矛盾的新陈代谢利益和有限的 补给品。此外，孕产妇的互动不是通过被动筛子发生的，而是积极的，而是 由胎盘动态策划，胎盘是一种具有自身生理需求的器官。因此是 显然，母亲，胎盘，胎儿或他们的稳态平衡的任何破坏 环境可能表现为挑战母体生理学（例如，先兆子痫）或 胎儿发育（例如，胎儿生长限制），或可能导致怀孕过早终止（例如， 早产）。胎盘的完整功能包括一组由胎盘生成的信号 滋养细胞并与母体和/或胎儿室进行通信。这些信号包括 激素（蛋白质，糖蛋白，类固醇激素）和生长因子，它们具有旁分泌和 内分泌对母体和可能是胎儿组织的作用。我们关于纳米层的新研究中心 （外部）基于沟通。这些外泌体是在人类滋养细胞和港口信号中产生的 这是对怀孕健康的隐居者。这些信号包括胎盘特异性microRNA（miRNA）， 我们最近表明，赋予对受体细胞的病毒抗性。这些miRNA也可能影响当地胎盘 生物过程，例如滋养细胞迁移和入侵。胎盘产生丰富的 目前未知的外泌体数量，其目标组织尚不清楚。而且， 胎盘外泌体将其货物运送到靶细胞，其细胞内功能的调节尚未 迄今已调查。因此，我们试图检验人类滋养细胞外泌体使用的假设 针对局部和远处靶向母体组织的特定摄取机制以及影响细胞功能。我们将 使用孕妇衍生的人类滋养细胞和外泌体检验我们的假设。对于那些 在人类中无法执行的实验，我们将使用经过适当验证的小鼠 对正在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 胎儿和母体之间至关重要的基于外泌体的交流机制 车厢。此外，由于可以通过血液进入胎盘外泌体，因此我们生成的数据 调查将引入调查人胎盘的新方法，并可能促进使用 外泌体作为胎盘功能障碍诊断的一部分，并指示基于纳米颗粒的新途径 疗法。