Biomarker for intellectual disability in children prenatally exposed to alcohol

这项申请是“胎儿酒精谱系障碍合作倡议”竞争性更新的一部分 (CIFASD)“响应RFA-AA-17-012。 产前酒精暴露所致胎儿酒精谱障碍的病理转归 (PAE)是毁灭性的和高度可变的，特别是关于在晚年生活中明显的认知和学习缺陷。 对这种赤字的早期干预对于最佳结果是必不可少的；然而，这些赤字的模式和规模 即使考虑到酒精暴露的水平，缺陷也不能预测，而酒精暴露本身很难准确 评估。因此，早期准确预测认知和行为问题风险的生物标志物对 建立有效的治疗方法。该项目旨在建立一种新的方法来识别这些生物标记物 预测患有FASD的儿童的风险。根据我们的初步数据，我们假设单细胞水平 血细胞样本中可检测到的表观遗传变化可作为预测认知障碍和糖尿病风险的生物标志物 学习障碍在其症状表现之前。通过采用尖端的细胞液滴技术，我们 我将使用PAE的小鼠模型(目标1)来检验这一假设，并检查这些生物标志物是否适用于 有PAE病史的人类患者(目标2)。桥本-鸟井实验室将进行单细胞液滴数字聚合酶链式反应- 以人和小鼠血液样本为基础的生物标记物分析(Drop-PCR)。鸟井实验室将收集这只老鼠 血液样本，执行全面的老鼠行为分析，并从统计上评估潜在的相关性 动物行为与Drop-PCR结果之间的关系。钱伯斯实验室将收集人体血液样本，进行 神经认知测试，并对这些测试分数和Drop-PCR之间的潜在相关性进行统计评估 结果。 该项目将允许在将生物标记物与综合评价联系起来进行关键评估 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 我们可能与CIFASD的其他研究合作，包括神经行为(Chambers)、遗传学(Foroud)和 变形学核心(琼斯)项目。使用对照动物研究的横断面方法(Eberhart和Parnell) 将提供基本的机械洞察力。我们识别的生物标记物和通过使用细胞因子研究获得的生物标记物 为相同的PAE患者生成的(Chambers)和miRNA(Weinberg)面板将提供一个难得的机会来测试这一点 准确预测PAE结局的联合生物标记物策略。通过利用CIFASD基础设施，这 该项目将开发创新的单细胞生物标记物，影响FASD研究和整个翻译科学。

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.