Biomarker for intellectual disability in children prenatally exposed to alcohol

产前接触酒精的儿童智力障碍的生物标志物

• 批准号: 9391732
• 负责人: KAZUE HASHIMOTO-TORII
• 金额: $ 26.18万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9391732
• 关键词: Accounting; Adolescent; Adult; Age; Animal Behavior; B-Lymphocytes; Behavior; Biological Markers; Blood; Blood Cells; Blood specimen; Brain; Cell Separation; Cells; Child; Cognitive; Collaborations; Control Animal; Data; Detection; Drops; Dysmorphology; Early Intervention; Elderly; Encapsulated; Epigenetic Process; Evaluation; Face; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Genetic; Human; Individual; Intellectual functioning disability; Laboratories; Learning; Link; Measures; Methods; MicroRNAs; Mus; Natural Killer Cells; Neonatal; Neurocognitive Deficit; Nursery Schools; Outcome; Pathologic; Patients; Pattern; Plasma; Postdoctoral Fellow; Problem behavior; Procedures; Reagent; Recording of previous events; Research; Research Infrastructure; Research Personnel; Risk; Sampling; School-Age Population; Severities; Structural defect; Technology; Testing; Therapeutic; Tissues; Translational Research; alcohol exposure; alcohol measurement; base; candidate marker; cell type; cohort; cytokine; digital; early detection biomarkers; effective therapy; improved; indexing; innovation; insight; learning ability; monocyte; motor learning; mouse model; neurobehavioral; neurobehavioral test; neurocognitive test; novel; novel marker; novel strategies; postnatal; predictive marker; prenatal exposure; response; stem

This application is a part of the competitive renewal for the "Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD)" in response to RFA-AA-17-012. Pathological outcomes of Fetal Alcohol Spectrum Disorder (FASD) stemming from prenatal alcohol exposure (PAE) are devastating and highly variable, especially in regards to cognitive and learning deficits apparent in later life. Early intervention for such deficits is imperative for optimal outcomes; however, the pattern and magnitude of these deficits are not predictive even when accounting for the level of alcohol exposure, which by itself is difficult to accurately assess. Therefore, early, and precise biomarkers for predicting the risk of cognitive and behavior problems are crucial for establishing an effective treatment. This project aims at establishing a novel approach to identifying such biomarkers for predicting the risk of children afflicted with FASD. Based on our preliminary data, we hypothesize that single-cell level epigenetic changes detectable in blood cell samples serve as biomarkers in predicting risks of cognitive and learning deficits before their symptomatic manifestations. By employing cutting-edge cellular droplet technology, we will test this hypothesis using the mouse model of PAE (Aim 1), and examine whether these biomarkers are applicable for human patients with a history of PAE (Aim 2). The Hashimoto-Torii lab will perform the single-cell droplet digital PCR- based biomarker analyses (drop-PCR) with both human and mouse blood samples. The Torii lab will collect the mouse blood samples, perform comprehensive mouse behavior analyses, and statistically evaluate potential correlations between the animal behaviors and drop-PCR results. The Chambers lab will collect the human blood samples, perform neurocognitive tests, and statistically evaluation of potential correlations between these test scores and the drop-PCR results. This project will allow for critical assessment in linking biomarkers with comprehensive evaluations of neurocognitive deficits, brain structural abnormalities and facial dysmorphology. In addition, these studies maximize the potential our collaborations with other CIFASD research including the neurobehavioral (Chambers), genetic (Foroud) and dysmorphology core (Jones) projects. Cross-sectional approaches using controlled animal studies (Eberhart and Parnell) will provide essential mechanistic insights. Our identified biomarkers and those obtained through studies using cytokine (Chambers) and miRNA (Weinberg) panels generated for the same PAE patients will provide a rare opportunity to test this combined biomarker strategy for accurate prediction of PAE outcomes. By capitalizing on CIFASD infrastructure, this project will develop innovative single-cell biomarkers that impact FASD research and translational science at large.

该应用程序是“胎儿酒精谱系合作计划的竞争性更新的一部分 （CIFASD）“响应RFA-AA-17-012。 胎儿酒精暴露导致的胎儿酒精谱系障碍（FASD）的病理结局 （PAE）是毁灭性的且高度可变的，尤其是在后来的认知和学习缺陷方面。 对于最佳结局，必须提早干预此类缺陷。但是，这些模式和大小 即使考虑到酒精暴露水平，赤字也不是可预测的，这本身难以准确 评估。因此，预测认知风险和行为问题的早期和精确的生物标志物对于 建立有效的治疗方法。该项目旨在建立一种新颖的方法来识别此类生物标志物 预测儿童患有FASD的风险。基于我们的初步数据，我们假设单细胞水平 在血细胞样本中可检测到的表观遗传变化是预测认知风险和 在症状表现之前学习缺陷。通过采用尖端的蜂窝液滴技术，我们 将使用PAE的鼠标模型（AIM 1）检验该假设，并检查这些生物标志物是否适用于 有PAE病史的人类患者（AIM 2）。 Hashimoto-Torii实验室将执行单细胞液滴数字PCR- 基于人类和小鼠血液样本的基于生物标志物分析（Drop-PCR）。 Torii实验室将收集鼠标 血液样本，进行全面的小鼠行为分析并统计评估潜在的相关性 在动物行为和Drop-PCR结果之间。钱伯斯实验室将收集人类血液样本，执行 神经认知测试以及对这些测试分数与Drop-PCR之间潜在相关性的统计评估 结果。 该项目将允许将生物标志物与对的全面评估联系起来进行批判性评估 神经认知缺陷，大脑结构异常和面部畸形学。另外，这些研究最大化 我们与其他CIFASD研究的合作有可能 畸形核心（琼斯）项目。使用受控动物研究（Eberhart和Parnell）的横断面方法 将提供基本的机械见解。我们确定的生物标志物以及通过使用细胞因子进行研究获得的生物标志物 （Chambers）和MiRNA（Weinberg）为同一PAE患者生成的面板将提供难得的测试机会 合并生物标志物策略以准确预测PAE结果。通过利用CIFASD基础设施， 项目将开发创新的单细胞生物标志物，影响FASD研究和转化科学。