Extracellular vesicles and their ncRNA cargo as markers of trophoblast injury

细胞外囊泡及其 ncRNA 货物作为滋养层损伤的标志物

• 批准号: 9269122
• 负责人: Yoel Sadovsky
• 金额: $ 72.54万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269122
• 关键词: Abruptio Placentae; Acoustics; Apoptotic; Arteries; Bioinformatics; Biological Assay; Biology; Biomedical Engineering; Biophysics; Biopsy; Blood; Blood Circulation; Blood Volume; Blood flow; Characteristics; Clinical; Communication; Data; Developmental Biology; Diagnosis; Diagnostic; Diffuse; Dimensions; Disease; Embryonic Development; Endoglin; Equilibrium; Evaluation; Excision; Fetal Death; Fetal Development; Fetal Growth; Fetal Growth Retardation; Fetal Tissues; Fetus; Functional disorder; Future; Gases; Glean; Gold; Health; Histologic; Hormones; Human; Injury; Interruption; Intervention; Investigation; Knowledge; Lab-On-A-Chips; Location; Machine Learning; Magnetic Resonance Imaging; Maternal Health; Maternal Physiology; Methods; MicroRNAs; Microfluidics; Molecular; Molecular Biology; Molecular Profiling; Monitor; Needle biopsy procedure; Nutrient; PGF gene; Pathology; Perinatal; Placenta; Placenta Diseases; Placental Biology; Plasma; Plasma Proteins; Positioning Attribute; Postpartum Period; Pre-Eclampsia; Predictive Value; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy-Associated Plasma Protein-A; Premature Birth; Production; Property; Provider; Research Institute; Shapes; Signal Transduction; Sorting - Cell Movement; Techniques; Technology; Testing; Therapeutic; Time; Tissue Differentiation; Training; Translations; Ultrasonography; Universities; Untranslated RNA; Venipunctures; Vesicle; Viscosity; Woman; adverse pregnancy outcome; base; biophysical properties; biophysical techniques; circular RNA; clinical care; clinical diagnostics; cost effective; design; exosome; experience; extracellular; extracellular vesicles; fetal; fitness; guided inquiry; high dimensionality; improved; in vivo; injured; innovation; mechanical properties; microvesicles; nanofabrication; nanomechanics; nanovesicle; novel; perinatal medicine; peripheral blood; pregnancy disorder; public health relevance; skills; stem; success; tomography; tool; transcriptome sequencing; trophoblast; viscoelasticity; wasting

 DESCRIPTION (provided by applicant): Throughout human pregnancy, the placenta is indispensable for embryonic development, fetal growth and tissue differentiation. The placenta also protects the fetus against diverse insults, while preserving maternal health. Placental dysfunction is commonly implicated in complications of pregnancy that challenge maternal physiology (e.g., preeclampsia) and fetal development (e.g., fetal death or fetal growth restriction) or that leads to preterm birth. Within the placenta, the trophoblast constitutes the outermost layer, which is directly bathed in maternal blood and therefore positioned to regulate maternal-fetal gas exchange, nutrient delivery, waste removal and the production of hormones, faithfully balancing fetal needs and maternal supply. Trophoblast damage, which is common in dysfunctional placentas, may interrupt the delicate maternal-fetal balance, cause clinical disease, and leave a lifelong mark on health. A fundamental challenge in perinatal medicine arises from our limited ability to diagnose placental disorders in real time and throughout pregnancy. However, the recent discovery, by ourselves and others, that (a) placental trophoblasts release distinctive micro- and nanovesicles into the maternal circulation and (b) these vesicles contain trophoblast-specific non-coding RNA cargo, created a new opportunity for assessing trophoblast health. These vesicles are actively released by trophoblasts throughout pregnancy, and thus serve as a venipuncture-accessible "natural biopsy" of trophoblasts, which can furnish information on trophoblast health in real time. Our established perinatal biology group at Magee- Womens Research Institute includes expertise in perinatal medicine and placental pathology, developmental and molecular biology, and bioinformatics. Inspired by these recent advances, we have partnered with an experienced group of bioengineers that includes experts from Carnegie Mellon University, MIT, and Penn State University, with unique skills in biophysics-based vesicle analytics, including microfluidics, nanomechanics, micro/nano fabrication and vesicle sorting using acoustic tweezers. Together, our new transdisciplinary group will use integrated molecular and biophysical methodologies to directly assess the use of trophoblast-derived extracellular vesicles from maternal plasma as revelatory of trophoblast health in real time and as a technique that may be employed throughout pregnancy. Our approach is comprehensive, centering on miRNAs as well as lncRNAs and circRNAs, analyzed in exosome nanovesicles, as well as microvesicles and apoptotic bodies. As each vesicle features a unique bimolecular and biophysical signature, we will deploy our machine learning- based training and testing pipeline to informatively integrate these distinct signals into an innovative diagnostic tool. Lastly, our deployment of affordable acoustic tweezers technology to sort trophoblastic vesicles will facilitate the translation of our advances into a new "lab on a chip" placental diagnostic technology, suitable for small blood volumes. This technology may not only denote trophoblast pathology, but has potential to identify those who may benefit from intervention and to monitor therapeutic success.

 描述（申请人提供）：在人类怀孕期间，胎盘对于胚胎发育、胎儿生长和组织分化是不可或缺的。胎盘还可以保护胎儿免受各种伤害，同时维护母亲的健康。胎盘功能障碍通常与妊娠并发症有关，这些并发症会挑战母体生理（例如先兆子痫）和胎儿发育（例如胎儿死亡或胎儿生长受限）或导致早产。在胎盘内，滋养层构成最外层，直接沐浴在母体血液中，因此负责调节母胎气体交换、营养输送、废物清除和激素产生，忠实地平衡胎儿需求和母体供应。滋养层损伤在功能失调的胎盘中很常见，可能会破坏微妙的母胎平衡，导致临床疾病，并给健康留下终生的印记。围产期医学面临的一个根本挑战是我们在整个怀孕期间实时诊断胎盘疾病的能力有限。然而，我们和其他人最近发现（a）胎盘滋养层向母体循环释放独特的微米和纳米囊泡，以及（b）这些囊泡含有滋养层特异性非编码RNA货物，为评估滋养层健康创造了新的机会。这些囊泡在整个怀孕期间由滋养层细胞主动释放，因此可以作为滋养层细胞的静脉穿刺“自然活检”，可以实时提供有关滋养层健康状况的信息。我们在玛吉妇女研究所建立的围产期生物学小组包括围产期医学和胎盘病理学、发育和分子生物学以及生物信息学方面的专业知识。受这些最新进展的启发，我们与经验丰富的生物工程师团队合作，其中包括来自卡内基梅隆大学、麻省理工学院和宾夕法尼亚州立大学的专家，他们在基于生物物理学的囊泡分析方面拥有独特的技能，包括微流体、纳米力学、微/纳米制造和使用声学镊子的囊泡分选。我们新的跨学科小组将共同使用综合分子和生物物理方法来直接评估来自母体血浆的滋养层衍生的细胞外囊泡的使用，作为滋养层健康的实时揭示，并作为一种可以在整个怀孕期间使用的技术。我们的方法是全面的，以 miRNA 以及 lncRNA 和 circRNA 为中心，在外泌体纳米囊泡、微囊泡和凋亡小体中进行分析。由于每个囊泡都具有独特的双分子和生物物理特征，我们将部署基于机器学习的训练和测试管道，将这些不同的信号信息丰富地整合到创新的诊断工具中。最后，我们部署经济实惠的声镊技术来分类滋养层囊泡，将有助于将我们的进步转化为新的“芯片实验室”胎盘诊断技术，适用于小血量。这项技术不仅可以表示滋养层病理学，而且有潜力识别那些可能从干预中受益的人并监测治疗的成功。