Biochemical pathways and biomarkers of alcohol injury in early human development

描述（由申请人提供）：本R21申请涉及酒精诱导组织损伤机制项目公告。胎儿酒精谱系障碍（FASD）是美国已知的导致出生缺陷和智力损伤的主要原因。酒精对发育中的神经元造成损伤的机制尚不完全清楚。这项研究提出了一种新的方法来揭示参与FASD发病的生化途径，并发现候选的临床生物标志物，以更好地诊断和治疗这种疾病。人类胚胎（hES）干细胞、神经前体和神经元的代谢组学将识别和测量哪些代谢物和途径因酒精损伤而显著改变。这些代谢物穿过血脑屏障和胎母界面，作为FASD早期诊断的候选生物标志物。接下来，该研究将研究酒精对细胞活力和人类神经发生功能方面的影响，特别强调5 -羟色胺能（5HT）神经元。5 -羟色胺能神经元是发育中的人脑中酒精损伤的一个重要但相对未被探索的候选细胞；这些神经元比其他亚型更容易受到环境的影响。5HT神经元在FASD儿童常见的认知障碍中发挥核心作用，例如学习、记忆、执行功能、运动技能、判断和注意力缺陷多动障碍。我们未来的目标是检查在受FASD影响的婴儿与健康个体的血液（血清）中检测到的候选生物标志物是否也发生了改变。最重要的是，本研究中发现的候选临床生物标志物可能有助于预防FASD，因为它们可以用于产前筛查，以识别有风险的孕妇及其受影响的后代。

DESCRIPTION (provided by applicant): This R21 application relates to the Mechanisms of Alcohol-Induced Tissue Injury program announcement. Fetal alcohol spectrum disorders (FASD) are the leading known cause of birth defects and mental impairment in the United States. The mechanisms of alcohol- induced damage to developing neurons are not completely understood. This study proposes a new alternative to unravel biochemical pathways that participate in the onset of FASD and discover candidate clinical biomarkers for better diagnosis and management of this disorder. Metabolomics of human embryonic (hES) stem cells, neural precursors and neurons will identify and measure which metabolites and pathways are significantly altered by alcohol injury. These metabolites, which cross the blood-brain barrier and fetal-maternal interface, serve as candidate biomarkers for early diagnosis of FASD. Next, the study will examine the effects of alcohol on cell viability and functional aspects of human neurogenesis with particular emphasis on serotonergic (5HT) neurons. Serotonergic neurons are an important but relatively unexplored candidate for alcohol injury in the developing human brain; these neurons are more susceptible to the effects of the environment than other subtypes. 5HT neurons play a central role in cognitive disorders that are common to children with FASD, such as deficits in learning, memory, executive functioning, motor skills, judgment and attention-deficit hyperactivity disorders. Our future goal is to examine if candidate biomarkers detected here are also altered in the blood (serum) of infants affected by FASD versus healthy individuals. Most importantly, the candidate clinical biomarkers discovered in this study may be contribute to prevention of FASD since they could be used in prenatal screening to identify pregnant women at risk and their affected offspring.