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（由适用提供）：通过人类怀孕，胎盘对于胚胎发育，胎儿生长和组织分化是必不可少的。胎盘还保护胎儿免受潜水员的侮辱，同时保留了物物生物健康。胎盘功能障碍通常是在怀孕并发症中实施的，这些并发症挑战了物物生理学（例如，前宾夕化）和胎儿发育（例如胎儿死亡或胎儿生长限制）或导致早产的胎儿发育（例如，胎儿死亡或胎儿生长限制）。在片剂中，滋养细胞构成了最外层的层，该层直接沐浴在母血中，因此定位于调节母亲狂热气体交换，营养递送，废物清除和骑马的产生，忠实地平衡了胎儿需求和母体供应。滋养细胞损害在功能失调的子宫集中很常见，可能会中断细腻的母亲平衡，引起临床疾病，并为健康留下终生标记。围产期医学的一个基本挑战是我们有限的实时诊断斑点疾病的能力有限。然而，最近的发现，我们自己和其他人，（a）斑点滋养细胞释放出独特的微型和纳米层释放到母体循环中，（b）这些蔬菜包含滋养细胞特异性的非编码RNA货物，为评估滋养细胞健康创造了新的机会。这些蔬菜在整个怀孕期间都由滋养细胞积极释放，因此可以作为拟齿剂的“自然活检”的滋养细胞，可以实时提供有关滋养细胞健康的信息。我们在Mageemens研究所建立的围产期生物学小组包括围产期医学和斑点病理学，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，我们与一群经验丰富的生物工程师合作，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，在基于生物物理学的蔬菜分析方面具有独特的技能，包括微基，包括微型机械，纳米力学，微型/纳米制造和蔬菜分类，使用声音宾夕法尼亚州。总之，我们的新跨学科组将使用综合的分子和生物物理方法直接评估来自母体血浆中滋养细胞衍生的细胞外蔬菜的使用，以实时揭示滋养细胞健康，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，在外部纳米层中分析，以及微泡和凋亡体。由于每个视频都具有独特的双分子和生物物理签名，因此我们将部署基于机器学习的培训和测试管道，以将这些不同的信号整合到创新的诊断工具中。最后，我们部署负担得起的镊子技术来分类滋养细胞蔬菜，将有助于将我们的进步转化为新的“芯片上的实验室” placenal诊断技术，适用于小血量。这项技术不仅可能表示滋养细胞病理学，而且有可能识别那些可能从干预中受益并监测治疗成功的人。