Exosome Based Placental Maternal Communication

项目摘要/摘要 怀孕是一个独特的时期，在这个时期，任何一个人类有机体固有的生物学复杂性 由快速发育的胎儿和成年母亲之间的亲密互动而指数放大 在怀孕的九个月中表现出显著的生理适应能力。重要的是，生物 这两个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 补给。此外，母婴之间的互动不是通过被动的筛子发生的，而是主动的和 由胎盘动态编排，胎盘是一个有自己一套生理需求的器官。因此，它是 显然，任何对母亲、胎盘、胎儿或其自身动态平衡的破坏 环境可能表现为一种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)，或者可能导致提前终止妊娠(例如， 早产)。胎盘的完整功能包括一组由胎盘产生的信号 滋养层细胞，并与母体和/或胎儿隔室沟通。这些信号包括 激素(蛋白质、糖蛋白、类固醇激素)和生长因子，它们具有旁分泌和 内分泌对母体组织的影响，可能还有对胎儿组织的影响。我们的新系列研究集中在纳米胶囊上 (外显体)为基础的交流。这些外切体是在人类滋养层细胞中产生的，并提供信号 这与怀孕健康密切相关。在这些信号中有胎盘特异的microRNAs(MiRNAs)， 我们最近发现，病毒对受体细胞具有抵抗力。这些miRNAs也可能影响局部胎盘 生物过程，如滋养层细胞迁移和入侵。而胎盘会产生丰富的 外切体的数量，其靶向组织目前尚不清楚。此外，通过哪些机制 胎盘外切体将其货物运送到靶细胞，但其细胞内功能的调节尚未 到目前为止一直在调查。因此，我们试图测试人类滋养层外小体使用 以母体组织为靶点的特定摄取机制，局部和远程，并影响细胞功能。我们会 使用人类滋养层细胞和来自孕妇的外切体来验证我们的假设。对于那些 不能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-胎盘和母体之间关键的、基于外体的通讯机制 车厢。此外，由于胎盘外切体可以通过血液获得，我们的数据产生了 调查将引入新的手段来研究人类胎盘，并可能促进使用 外切体作为胎盘功能障碍诊断的一部分，并为纳米颗粒为基础的新途径指明了方向 治疗学。

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.