MicroRNAs as Biomarkers of Exposure and Effect in Fetal Alcohol Spectrum Disorders

MicroRNA 作为胎儿酒精谱系疾病暴露和影响的生物标志物

• 批准号: 9069661
• 负责人: SANDRA W. JACOBSON
• 金额: $ 21.89万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069661
• 关键词: Ablation; Address; Adverse effects; Affect; Age; Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Back; Behavioral; Biological; Biological Assay; Biological Markers; Birth; Blood; Brain; Child; Clinical Data; Code; Cognitive; Color; Cross-Cultural Comparison; Data; Development; Diagnosis; Disease; Early Intervention; Endocrine; Ethanol; Ethnic group; Exhibits; Exposure to; Face; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal Alcohol Syndrome; Fetal alcohol effects; Fetus; Future; Growth; Health; High Prevalence; Human; Incidence; Infant; International; Interview; Lead; Liquid substance; Magnetic Resonance Imaging; Measurement; Measures; Meconium; Mediating; Metabolic; MicroRNAs; Modeling; Neonatal; Neurodevelopmental Disability; Newborn Infant; Outcome; Pattern; Perinatal Exposure; Phenotype; Plasma; Population; Postpartum Period; Pregnancy; Prospective Studies; Public Health; RNA; Recording of previous events; Recruitment Activity; Repressor Proteins; Research; Research Personnel; Resources; Role; Sampling; Sensitivity and Specificity; Severities; Sheep; South Africa; Statistical Models; Stream; Testing; Time; TimeLine; Tissues; Translations; Zebrafish; alcohol consumption during pregnancy; alcohol effect; alcohol exposure; base; biomarker development; circulating microRNA; clinical practice; cognitive function; cognitive testing; cohort; craniofacial; diagnostic biomarker; drinking; extracellular; fetal; in utero; infancy; innovation; meetings; neurobehavioral; neurodevelopment; non-genetic; novel; novel therapeutics; postnatal; potential biomarker; pre-clinical; screening; social stigma

 DESCRIPTION (provided by applicant): Diagnosis of fetal alcohol spectrum disorders (FASD) is difficult in infancy and in the many affected nonsyndromal children, who do not manifest facial stigmata. Promising meconium- and blood-based metabolic biomarkers have been developed. However, these markers of exposure are only moderately predictive of adverse effects and are measured in biological substrates that can be obtained only during limited developmental windows. We will assess the biomarker potential of circulating plasma microRNAs (cirmiRNAs), small non-protein-coding RNAs that are secreted into the blood stream, can be acquired at different postnatal ages, and may serve as endocrine factors. PI Miranda and colleagues have found that in utero maternal alcohol exposure leads to an altered expression pattern of cirmiRNAs in newborn sheep, including a previously identified ethanol-sensitive miRNA, miR-9, the ablation of which leads to a zebra fish phenotype similar to that seen in prenatal alcohol exposure. Based on these pre-clinical data, we hypothesize that prenatal alcohol exposure leads to an altered expression pattern of cirmiRNAs in humans that may serve as a biomarker for exposure and that specific cirmiRNAs altered by prenatal alcohol exposure will also serve as biomarkers for fetal alcohol-related deficits in neurodevelopment and/or growth. To test this hypothesis, we propose to screen for cirmiRNA biomarkers in a unique cohort of alcohol-exposed infants from the Cape Colored (mixed ancestry) population in Cape Town, South Africa, which has among the highest worldwide incidence of fetal alcohol syndrome. PI Jacobson and colleagues are currently conducting a study of infants from this population, which includes detailed maternal alcohol consumption interviews obtained prospectively during pregnancy, FASD diagnosis by expert dysmorphologists, neonatal structural MRI data, physical growth measurements, and cognitive assessments at 6.5 and 12 mo. postpartum. Plasma samples will be obtained for miRNA profiling from 30-35 heavily exposed and 30-35 control infants from this cohort at 2 wk. and 6.5 mo. postpartum. Using real-time PCR arrays, we will attempt to identify a profile of cirmiRNAs that distinguish alcohol-exposed infants from controls. We will then determine whether the cirmiRNAs that are altered by alcohol exposure predict fetal alcohol-related developmental outcomes, including smaller birth size, structural brain anomalies, poorer cognitive function, and FASD diagnosis. This proposal addresses a critical need for developing diagnostic biomarkers for both prenatal alcohol exposure and effect from samples acquired during and beyond the neonatal period. It is responsive to PA-13-197, "The Role of Extracellular RNA in Mediating the Health Effects of Alcohol," with its specific focus on biomarker development. Evidence of distinctive cirmiRNAs profiles in FASD has potential to uncover novel endocrine mechanisms mediating effects of fetal alcohol exposure that may provide the basis for development of novel therapies.

 描述（由适用提供）：婴儿期和许多受影响的非龙族儿童的诊断很难诊断出胎儿酒精谱系障碍（FASD），他们不表现出面部污名。已经开发了有希望的胎粪和血液代谢生物标志物。但是，这些暴露的标记仅是对不良反应的适度预测，并且在有限的发育窗口中只能获得的生物基底物中测量。我们将评估循环等离子体microRNA（cirirnas）的生物标志物潜力，可以分泌到血流中的小型非蛋白质编码RNA，可以在不同的产后年龄获得，并且可以用作内分泌因子。皮·米兰达（Pi Miranda）及其同事发现，在子宫内物物酒精暴露会导致新生绵羊中cirirnas的表达模式改变，包括先前鉴定的乙醇敏感的miRNA，miR-9，其消融导致与斑马鱼表型相似的斑马鱼表型。基于这些临床前数据，我们假设产前酒精暴露会导致人类中cirirnas的表达模式改变，这可能是暴露的生物标志物，并且在产前酒精暴露中改变的特定cirrnas也将作为胎儿酒精相关缺乏的生物标志物在与神经相关的胎儿相关性缺乏症中也将是神经相关的和/或生长。为了检验这一假设，我们建议在南非开普敦开普敦（Cape）有色人种（混合血统）人口的独特饮酒婴儿中筛选cirnna生物标志物，这是全球最高的胎儿酒精综合征事件之一。 Pi Jacobson及其同事目前正在对该人群的婴儿进行研究，其中包括怀孕期间前瞻性获得的详细材料饮酒访谈，专家畸形学家FASD诊断，新生儿结构MRI数据，身体生长测量以及6.5和12 mo的认知评估。产后。将获得从30-35个大暴露的miRNA分析和30-35个对照婴儿的miRNA样品，该分析在2周时从该队列中获得。和6.5 mo。产后。使用实时PCR阵列，我们将尝试确定将酒精暴露婴儿与对照组区分开的cirirnas的特征。然后，我们将确定酒精暴露改变的cirirnas是否可以预测胎儿酒精相关的发育结果，包括较小的出生率，结构性脑异常，认知功能较差和FASD诊断。该提案解决了开发诊断生物标志物的至关重要的需求，以期在新生儿期间和之后获得的样品中获得的样品。它对PA-13-197的反应敏感，“细胞外RNA在介导酒精的健康作用中的作用”，其特定的重点是生物标志物的发展。 FASD中独特的cirrnas谱的证据有可能发现介导胎儿酒精暴露作用的新型内分泌机制，这可能为开发新疗法提供了基础。

项目成果

Infant circulating MicroRNAs as biomarkers of effect in fetal alcohol spectrum disorders.

• DOI: 10.1038/s41598-020-80734-y
• 发表时间: 2021-01-14
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Mahnke AH;Sideridis GD;Salem NA;Tseng AM;Carter RC;Dodge NC;Rathod AB;Molteno CD;Meintjes EM;Jacobson SW;Miranda RC;Jacobson JL
• 通讯作者: Jacobson JL