Biochemical pathways and biomarkers of alcohol injury in early human development

人类早期发育中酒精损伤的生化途径和生物标志物

基本信息

批准号：
7532445
负责人：
GABRIELA G CEZAR
金额：
$ 17.63万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7532445
关键词：
Address Adult Affect Alcohol-Induced Disorders Alcohol-Induced Neurotoxicity Alcohol-Related Neurodevelopmental Disorder Alcohols Animal Model Apoptosis Applications Grants Attention deficit hyperactivity disorder Biochemical Biochemical Pathway Biological Markers Blood - brain barrier anatomy Blood Circulation Brain Caring Cell Death Cell Survival Cells Child Clinic Clinical Code Cognition Disorders Congenital Abnormality Data Development Diagnosis Diagnostic Dietary Supplementation Disease Management Disruption Dopamine Early Diagnosis Embryo Environment Ethanol Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Folic Acid Funding Funding Opportunities Future Goals High Risk Woman Human Human Development Hydrogen Peroxide Impaired cognition Impairment In Vitro Individual Infant Injury Intervention Judgment Knowledge Kynurenine Label Learning Mass Spectrum Analysis Maternal-Fetal Exchange Measures Memory Metabolic Metabolic Pathway Methods Mitotic Modeling Monitor Motor Skills NIH Program Announcements National Institute on Alcohol Abuse and Alcoholism Nature Neural Tube Defects Neurites Neurodevelopmental Disorder Neurons Numbers Outcome Oxidative Stress Pathway interactions Play Pregnant Women Prevalence Prevention Psyche structure Publishing Reporting Research Risk Role Screening procedure Sentinel Serotonin Serum Services Severities Specificity Spinal Dysraphism Staging Statistically Significant Technology Testing Tissues Translating Translational Research Translations Tubulin United States United States National Institutes of Health Universities WA01 cell line WA09 Cell Line Wisconsin alcohol effect alcohol exposure base comparative drinking executive function gamma-Aminobutyric Acid human embryonic stem cell human embryonic stem cell line improved in utero in vivo metabolomics nerve stem cell nestin protein neurodevelopment neurogenesis neurotoxic prenatal prevent relating to nervous system repaired small molecule stem synaptogenesis tool valproate

项目摘要

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.

描述（由申请人提供）：此 R21 申请涉及酒精引起的组织损伤机制计划公告。胎儿酒精谱系障碍 (FASD) 是美国已知的导致出生缺陷和精神障碍的主要原因。酒精对发育中的神经元造成损害的机制尚不完全清楚。这项研究提出了一种新的替代方案来解开参与 FASD 发病的生化途径，并发现候选临床生物标志物，以更好地诊断和管理这种疾病。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着改变。这些代谢物穿过血脑屏障和胎儿-母体界面，可作为 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，特别关注血清素能 (5HT) 神经元。血清素能神经元是人类大脑发育过程中酒精损伤的重要但相对未经探索的候选者。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着核心作用，例如学习、记忆、执行功能、运动技能、判断力和注意力缺陷多动障碍等缺陷。我们未来的目标是检查此处检测到的候选生物标志物在受 FASD 影响的婴儿的血液（血清）中是否也与健康个体相比发生了改变。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，因为它们可用于产前筛查，以识别有风险的孕妇及其受影响的后代。