Exosome Based Placental Maternal Communication

基于外泌体的胎盘母体通讯

• 批准号: 10565690
• 负责人: Yoel Sadovsky
• 金额: $ 40.12万
• 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/10565690
• 关键词: Adult; Affect; Allografting; Apoptotic; Attenuated; Bathing; Biological; Biological Process; Biopsy; Blood; Bulla; Cell Line; Cell membrane; Cell physiology; Cells; Chromosome 19; Circulation; Clinical; Communication; Cytomegalovirus; DNA Viruses; Data; Diagnostic; Dimensions; Disease; Distant; Endocrine; Endosomes; 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; Invaded; Investigation; Knowledge; 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; Viral Physiology; Virus Diseases; Waste Products; Work; cell type; design; engineered exosomes; exosome; experimental study; fetal; human pathogen; in vivo; interest; lipidomics; microRNA delivery; 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.

项目总结/摘要 怀孕是一个独特的时期，在这一时期，任何单一的人类机体的固有生物复杂性都是 一个快速发育的胎儿和一个成年母亲之间的亲密互动， 在怀孕的九个月里表现出了显著的生理适应性。重要的是，生物 两种生物体的利益并不总是一致的，反映了相互冲突的代谢利益和有限的 用品.此外，母胎相互作用不是通过被动的筛子发生的，而是主动地， 胎盘是一个有着自己生理需求的器官。因此 显然，母亲、胎盘、胎儿或其 环境可能表现为挑战母体生理学的临床疾病（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一组由胎盘产生的信号， 滋养层中的细胞，并与母体和/或胎儿隔室连通。这些信号包括 激素（蛋白质、糖蛋白、类固醇激素）和生长因子，它们具有旁分泌， 对母体组织以及可能对胎儿组织的内分泌影响。我们新的研究方向是纳米囊泡 （外泌体）为基础的通信。这些外泌体产生于人类滋养层细胞， 与孕期健康密切相关的疾病在这些信号中有胎盘特异性微RNA（miRNAs）， 我们最近发现，它能使受体细胞产生病毒抵抗力。这些miRNAs也可能影响局部胎盘 生物过程，如滋养层迁移和入侵。当胎盘产生大量的 外泌体的数量，其靶组织目前未知。此外， 胎盘外泌体将它们的货物递送到靶细胞，并且它们的细胞内功能的调节没有 至今被调查。因此，我们试图检验人类滋养层细胞外泌体使用 特定的摄取机制，以靶向母体组织，局部和远程，并影响细胞功能。我们将 使用人类滋养层细胞和来自孕妇的外来体来验证我们的假设。对于那些 在无法在人类中进行的实验中，我们将使用已被验证为适当的小鼠 模拟所研究的人类过程。最终，我们的数据将阐明以前未知的 胎儿-胎盘和母体之间基于外来体的重要通讯机制 隔间此外，由于胎盘外泌体可通过血液接触，因此我们的研究人员生成的数据显示， 研究将引入新的手段来研究人类胎盘，并可能促进使用 外泌体作为胎盘功能障碍诊断的一部分，并指出了基于纳米颗粒的新途径 治疗学