Developing Extracellular Vesicle Based MPRINT Translational Resource Platform for Monitoring Therapeutics Response During Pregnancy

开发基于细胞外囊泡的 MPRINT 转化资源平台，用于监测妊娠期间的治疗反应

• 批准号: 10747545
• 负责人: Maged Costantine
• 金额: $ 83.32万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-06 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747545
• 关键词: Affect; Alkaline Phosphatase; American College of Obstetricians and Gynecologists; Area; Aspirin; Biological Markers; Birth; Case Study; Cells; Characteristics; Childhood; Clinical; Clinical Drug Development; Collection; Communities; Data; Dependence; Development; Dose; Drug Evaluation; Endothelium; Exclusion; Fetal Growth Retardation; Fetus; Foundations; Funding; Gestational Age; Goals; Health; Iatrogenesis; Individual; Inflammatory; Infrastructure; Institutional Review Boards; Investigation; Lactation; Maternal Mortality; Maternal-Fetal Medicine Units Network; Mediating; Modeling; Monitor; National Institute of Child Health and Human Development; Neonatal Mortality; Ohio; Orphan; Outcome; Patients; Persons; Pharmaceutical Preparations; Physiological; Placenta; Plasma; Play; Populations at Risk; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Premature Birth; Prevention; Preventive treatment; Professional Organizations; Proteins; Proteome; Randomized, Controlled Trials; Recommendation; Research; Research Design; Resources; Risk; Role; Safety; Sampling; Second Pregnancy Trimester; Seminal; Services; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapeutic Research; Therapeutic Trials; Third Pregnancy Trimester; Time; Translational Research; United States; United States National Institutes of Health; United States Preventative Services Task Force; Universities; adverse pregnancy outcome; biobank; clinical care; cohort; design; differential expression; dosage; drug efficacy; exosome; extracellular vesicles; fetal; fetal drug exposure; improved; in vivo; innovation; insight; maternal morbidity; maternal outcome; neonatal morbidity; novel; novel marker; particle; patient advocacy group; pregnancy health; pregnant; prognostic; prospective; recruit; response; specific biomarkers; success; translational therapeutics; treatment response; trophoblast

ABSTRACT Pregnant and lactating people remain therapeutic orphans as they are excluded from the vast majority of clinical drug development and therapeutic trials. Moreover, current practices in drug evaluation in pregnancy have been hindered by the lack of effective biomarkers and innovative study designs. There is a need to develop novel placental-specific biomarkers in order to assess placental function and response to therapeutics, as a way to inform on their safety and efficacy. An example of these novel biomarkers is placental (fetal) specific extracellular vesicles (EVs). Recent advances in characterizing the cargo content of these EVs demonstrated their potential to be used as placental biomarkers. We have shown using funding support from the MPRINT that fourteen proteins found in EVs significantly correlated with aspirin use (FDR<0.1) in at-risk people, but that more power is needed to confidently assess the relationship with aspirin dosage and pregnancy outcomes. In addition, prior studies showed that aspirin affects endothelial and trophoblast cells, thus potentially modulating exosome derived from these cells and their cargo contents. Leveraging our prior proof of principle success, previously collected, and ongoing collection of maternal plasma from people at-risk of preeclampsia (PE) receiving 81mg or 162mg of aspirin daily and low-risk people at the Ohio State University, we are submitting this application with the overarching goal to develop a novel platform to augment the MPRINT resources using exosome profiling, as novel biomarkers, to monitor placental mediated adverse pregnancy outcomes and response to therapeutics. For this, we will use PE as a hallmark of these outcomes and aspirin as the therapeutic agent to show case the utility of the platform. In this study, we will test the hypothesis that differential expression of EVs proteome cargo is associated with placental and pregnancy health in response to aspirin treatment at different gestational periods. We will test the following specific aims: 1) Validate our preliminary proteome data and model using larger cohort from additional biobanked samples of at-risk people receiving 81mg or 162 mg aspirin, characterize fetal specific EVs (placental alkaline phosphatase [PLAP] +ve) isolated from maternal plasma, and determine the differences in between the maternal vs. fetal EV cargo difference with aspirin treatment; and 2) Determine the changes associated with EV proteome profile (maternal and fetal) in at-risk people receiving aspirin prospectively and correlate with clinical outcomes (development of PE) and angiogenic and inflammatory biomarkers associated with PE. This project has the potential to play a seminal role in the development of a novel platform for therapeutics research in pregnancy. This translational research platform will substantially add to the MPRINT Network repertoire and be available for scientific community through the already established relationship of the team with other networks such as the Maternal Fetal Medicine Units Network, MPRINT, and the Foundation of the NIH.

抽象的 怀孕和哺乳的人仍然是治疗性孤儿，因为他们被排除在绝大多数 临床药物开发和治疗试验。此外，当前的药物评估做法 由于缺乏有效的生物标志物和创新研究设计所阻碍。有必要 开发新颖的胎盘特异性生物标志物，以评估胎盘功能和对治疗剂的反应， 作为告知他们的安全性和功效的一种方式。这些新型生物标志物的一个例子是胎盘（胎儿） 特定的细胞外囊泡（EV）。表征这些电动汽车的货物含量的最新进展 证明了它们被用作胎盘生物标志物的潜力。我们已经表明了使用的资金支持 EV中发现的14种蛋白质与阿司匹林使用（FDR <0.1）显着相关的mprint 人们，但是需要更多的权力来自信地评估与阿司匹林剂量的关系和 怀孕结果。此外，先前的研究表明，阿司匹林会影响内皮细胞和滋养细胞， 因此，可能调节源自这些细胞及其货物含量的外泌体。利用我们的先验 以前收集的原则成功证明，以及持续的孕产妇等离子体。 俄亥俄州立大学每天接受81mg或162mg阿司匹林和低风险的人接受前斜率（PE） 大学，我们正在提交此应用程序，其总体目标是开发一个新颖的平台来增强 使用外泌体分析作为新型生物标志物来监测胎盘介导的不良的MPRINT资源 怀孕结果和对治疗剂的反应。为此，我们将使用PE作为这些结果的标志 阿司匹林作为治疗剂，以显示平台的实用性。在这项研究中，我们将测试 假设EV的差异表达蛋白质组货物与胎盘和妊娠有关 在不同的妊娠期对阿司匹林治疗的响应。我们将测试以下特定目标： 1）使用来自其他生物群的较大同类样品验证我们的初步蛋白质组数据和模型 胎儿特异性电动汽车（胎盘碱） 磷酸酶[PLAP] +VE）从母体血浆中分离出来，并确定 孕产妇与胎儿EV货物的差异与阿司匹林治疗； 2）确定与 在危险中接受阿司匹林的高危人中的EV蛋白质组概况（母体和胎儿），并与之相关 与PE相关的临床结果（PE的发展）以及血管生成和炎症生物标志物。这 项目有可能在开发新型治疗平台的发展中发挥精确作用 在怀孕。这个转化研究平台将大大增加Mprint网络曲目和 通过团队已经建立的与其他人的关系，可以为科学界提供 诸如孕产妇医学单位网络，mprint和NIH的基础等网络。