Extracellular Vesicles as a Link Between Placental and Renal Dysfunction in Preeclampsia

细胞外囊泡作为先兆子痫胎盘和肾功能障碍之间的联系

• 批准号: 10266768
• 负责人: Priyadarshini Pantham
• 金额: $ 6.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10266768
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Affect; Apoptosis; Biological; Biological Markers; Biology; Blood Circulation; Brain; Cells; Characteristics; Childbirth; Chromosomes; Clinical; Clinical Research; Coupled; Data; Developed Countries; Development; Diagnosis; Disease; Disease Pathway; Ductal Epithelial Cell; Epithelial Cells; Etiology; Excretory function; Failure; Fetal Mortality Statistics; Functional disorder; Genetic Transcription; Gestational Age; Goals; Health Care Costs; High Performance Computing; Human; Hypertension; Hypoxia; Immune response; Immunohistochemistry; In Vitro; Incidence; Injury; Kidney; Kidney Diseases; Libraries; Link; Lipids; Liver; Lung; Machine Learning; Maternal Mortality; Mentors; Messenger RNA; Methods; MicroRNAs; Molecular; Molecular Disease; Morbidity - disease rate; Mus; Nephrons; Nucleic Acids; Organ; Pathogenesis; Pathologic; Pathology; Phase; Placenta; Play; Population; Population Heterogeneity; Pre-Eclampsia; Pregnancy; Process; Proteins; Proteinuria; RNA; Research; Role; Sampling; Small RNA; Source; Stress; Syndrome; Techniques; Technology; Testing; Tissues; Transcript; Tubular formation; Urine; Woman; associated symptom; biobank; cell injury; cell type; clinically relevant; early onset; endothelial dysfunction; experimental study; extracellular vesicles; improved; innovation; kidney dysfunction; maternal serum; mortality; multidisciplinary; neonatal morbidity; novel; personalized medicine; pregnancy disorder; premature; prevent; response; stillbirth; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; uptake; urinary

PROJECT SUMMARY Preeclampsia (PE) is a devastating hypertensive disorder of pregnancy that is a leading cause of maternal and fetal mortality and morbidity worldwide. It affects 2-10% of women and accounts for 16% of maternal deaths related to childbirth in developed countries. PE is difficult to study because it is a multifactorial disorder with varying molecular mechanisms associated with the development of the spectrum of clinical symptoms associated with early onset, late onset, and severe PE. A personalized medicine approach applied to dissecting the underlying mechanisms of PE may be beneficial to reduce clinical incidence of this devastating syndrome. The placenta plays a key role in the development of PE, leading to widespread maternal endothelial dysfunction, hypertension, and systemic multi-organ failure in PE. Extracellular vesicles (EVs) containing protein, RNA, and lipid cargo are continuously extruded from the placenta, and are capable of interacting with maternal organs including the kidney. PE is primarily associated with placental and renal dysfunction, and PE is the most common cause of acute kidney injury during pregnancy. However, no studies have investigated the potential of placenta-derived RNA cargo as a link between placental and renal dysfunction in PE. Urinary EVs are derived from multiple tissue types and represent a trove of biomarkers that are increasingly being utilized to diagnose renal disorders. Further, urine samples can be obtained throughout pregnancy non-invasively and could potentially be utilized to identify biomarkers related to placental dysfunction in PE. In the proposed research, during the mentored phase, cutting-edge RNA-Seq technology coupled with computational biological and machine learning approaches will be applied to profile the transcriptome of urinary EVs in women with PE compared to normal pregnancy. Preliminary data indicates that it is possible to isolate and profile the transcriptome of urinary EVs from maternal urine throughout normal gestation, and that placenta-derived and placenta-specific mRNA and miRNA can be detected within the urinary EV population. This presents a novel technique that has potential to identify biomarkers as well as provide information on placental dysfunction in PE in a non-invasive manner. During the independent phase, the candidate will utilize an in vitro approach to investigate the effect of uptake of placenta-derived EVs with miRNA cargo associated with PE on the function of proximal tubule epithelial cells and cortical collecting duct cells. These two renal-specific cell types are involved in tubular reabsorption in the nephron, a process that is compromised leading to increased excretion of protein in the urine in some preeclamptic pregnancies. This proposal is multidisciplinary, utilizing basic biology, clinical research, and high-performance computing applied to investigating placental dysfunction in PE. These experiments are significant because they will generate novel information on the role of placenta- derived EVs in renal dysfunction in PE, as well as point the way towards preventative and therapeutic targets that may be transformative and clinically relevant.

项目摘要 子痫前期（PE）是一种毁灭性的妊娠高血压疾病，是母亲和孕产妇的主要原因 全球胎儿死亡率和发病率。它影响2-10％的妇女，占孕产妇死亡的16％ 与发达国家分娩有关。 PE很难学习，因为它是一种多因素疾病， 与临床症状谱的发展相关的不同分子机制 与早期发作，晚发和严重的PE相关。采用个性化医学方法 解剖PE的基本机制可能有益于减少这种毁灭性的临床发生率 综合征。胎盘在PE的发展中起关键作用，导致广泛的母体内皮 PE中的功能障碍，高血压和全身性多器官故障。包含细胞外囊泡（EV） 蛋白质，RNA和脂质货物连续挤出胎盘，并能够与 孕产妇器官在内。 PE主要与胎盘和肾功能障碍以及PE有关 是怀孕期间急性肾脏损伤的最常见原因。但是，没有研究调查 PE中胎盘衍生的RNA货物作为胎盘和肾功能障碍之间的联系。尿路电动汽车 来自多种组织类型，代表越来越多地使用的生物标志物 诊断肾脏疾病。此外，在整个怀孕期间都可以非侵入性地获得尿液样本，并且 有可能利用用于识别与PE中胎盘功能障碍有关的生物标志物。在提议中 研究，在指导阶段，尖端的RNA-seq技术和计算生物学 和机器学习方法将应用于PE女性的尿路电动汽车的转录组 与正常怀孕相比。初步数据表明可以隔离并配置 在整个正常妊娠期间，尿液尿液的尿电动汽车转录组，以及胎盘衍生的和 可以在尿EV群中检测到胎盘特异性mRNA和miRNA。这是一本小说 具有识别生物标志物并提供有关胎盘功能障碍的信息的技术 PE以非侵入性方式。在独立阶段，候选人将利用一种体外方法 研究与PE相关的miRNA货物对胎盘衍生的EV的摄取对功能的影响 近端小管上皮细胞和皮质收集导管细胞。这两种肾脏特异性细胞类型是 参与肾单位中的管状重吸收，这一过程受到损害，导致排泄增加 一些先兆子痫妊娠的尿液中的蛋白质。该建议是多学科的，利用基本 生物学，临床研究和高性能计算应用于研究胎盘功能障碍 PE。这些实验很重要，因为它们将产生有关胎盘作用的新信息 PE中肾功能障碍的EVS，以及通向预防和治疗靶标的道路 这可能具有变革性和临床相关。