Biomarker for intellectual disability in children prenatally exposed to alcohol

此应用程序是“胎儿酒精谱系障碍合作倡议”竞争性更新的一部分 （CIFASD）”以响应RFA-AA-17-012。 产前酒精暴露所致胎儿酒精谱系障碍（FASD）的病理结局 (PAE)是毁灭性的和高度可变的，特别是在以后的生活中明显的认知和学习缺陷方面。 对这种缺陷的早期干预对于最佳结果至关重要;然而，这些缺陷的模式和程度 即使考虑到酒精暴露水平，赤字也无法预测，因为酒精暴露水平本身很难准确 评估。因此，早期和精确的生物标志物预测认知和行为问题的风险是至关重要的， 建立有效的治疗。该项目旨在建立一种新的方法来识别这种生物标志物， 预测儿童患FASD的风险。根据我们的初步数据，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可作为预测认知和认知障碍风险的生物标志物。 在症状出现之前就有学习障碍。通过采用尖端的细胞液滴技术，我们 将使用PAE的小鼠模型来测试这一假设（目的1），并检查这些生物标志物是否适用于 有PAE病史的人类患者（目的2）。桥本鸟居实验室将进行单细胞液滴数字PCR- 基于生物标志物的分析（drop-PCR），使用人和小鼠血液样品。鸟居实验室将收集老鼠 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， 动物行为和drop-PCR结果之间的关系。钱伯斯实验室将收集人类血液样本， 神经认知测试，并统计评估这些测试分数和drop-PCR之间的潜在相关性 结果 该项目将允许在将生物标志物与全面评价联系起来方面进行关键评估， 神经认知缺陷、脑结构异常和面部畸形。此外，这些研究最大限度地 潜在的合作，我们与其他CIFASD研究，包括神经行为（钱伯斯），遗传（Foroud）和 异形核心（琼斯）项目。采用对照动物研究的横断面方法（Eberhart和帕内尔） 将提供基本的机械见解。我们鉴定的生物标志物和通过使用细胞因子的研究获得的生物标志物 针对相同PAE患者生成的Chambers（钱伯斯）和miRNA（温伯格）样本组将为检验这一点提供难得的机会 联合生物标志物策略，用于准确预测PAE结局。通过利用CIFASD基础设施， 该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。

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.