Development of an Epigenetic Biomarker for Prediction of Fetal Alcohol Spectrum D

开发用于预测胎儿酒精谱 D 的表观遗传生物标记

• 批准号: 8642950
• 负责人: Aileen Estelle Baldwin
• 金额: $ 16.23万
• 依托单位: U.S. DRUG TESTING LABORATORIES, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8642950
• 关键词: Adult; Adverse effects; Affect; Alcohol abuse; Alcohols; Analytical Toxicology; Behavioral; Biological Assay; Biological Markers; Birth; Blood; Brain; Child; Congenital Abnormality; Coupling; DNA; DNA Methylation; DNA analysis; Detection; Development; Developmental Disabilities; Diagnosis; Early Intervention; Early treatment; Embryonic Development; Epigenetic Process; Exhibits; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; First Pregnancy Trimester; Genes; Genetic Screening; Genome; Goals; Incidence; Infant; Laboratories; Methods; Methylation; Modification; Neonatal; Neonatal Alcohol Exposure; Neonatal Screening; Neurologic; Newborn Infant; Outcome; Pattern; Phase; Play; Pregnancy; Prevalence; Research; Risk; Role; Sampling; Scanning; Schools; Site; Source; Spottings; Substance Abuse Detection; Technology; Teratogens; Time; United States; alcohol exposure; alcohol screening; base; candidate selection; drug testing; effective intervention; effective therapy; epigenetic marker; fetal; fetal drug exposure; high risk; in utero; innovation; medical specialties; minimally invasive; neonate; neurobehavioral; novel; phase 1 study; phase 2 study; phosphatidylethanol; prenatal; programs; public health relevance; research and development; screening; treatment program

PROJECT SUMMARY Prenatal alcohol exposure is the leading preventable cause of birth defects in the United States, producing an array of neurological, behavioral and physical abnormalities collectively known as fetal alcohol spectrum disorders (FASD). Early intervention and treatment programs have been shown to reduce some of the long-term adverse effects, but this is dependent on identifying children at risk of fetal damage which is not detected in most cases. Many children affected by FASD do not exhibit obvious physical indications of prenatal alcohol-associated birth defects, creating challenges in making timely and accurate diagnoses. There is a critical need for development of biomarkers that can detect babies heavily exposed to alcohol throughout pregnancy, particularly during the first trimester when the fetal brain is most vulnerable to teratogens, to predict those at risk for developing the neurobehavioral and developmental disabilities associated with FASD. Prenatal alcohol exposure has been shown to alter DNA methylation patterns of genes known to play important roles in development and contribute to abnormal embryonic development, suggesting that alcohol-associated alterations in DNA methylation profiles, identified from neonatal blood spot samples, could be used as an alcohol biomarker in neonates. Coupling the technology United States Drug Testing Laboratories has developed for detection of the direct alcohol biomarker phosphatidylethanol (PEth) in blood spots with screening epigenetic changes associated with prenatal alcohol exposure provides an innovative approach to examine novel biological markers of alcohol exposure occurring throughout pregnancy that may be predictive of fetal damage. The objective of this Phase I project is to determine the feasibility of using neonatal blood spots to screen alcohol-induced DNA methylation alterations and establish whether these epigenetic modifications correlate with detection of PEth. The selection of candidate regions of differential methylation will be determined by whole-genome methylation scanning of DNA from neonatal blood spot samples collected from infants with known exposure to alcohol in utero and comparing them with non- exposed controls. If prenatal alcohol exposure is significantly associated with a defined set of differentially methylated DNA sites, the feasibility of using epigenetic markers to detect newborns at risk of fetal damage will have been established and these epigenetic patterns could be further examined as possible predictive biomarkers of FASD. Development and implementation of a quantitative DNA methylation screening assay, to analyze sites of differential methylation identified in this Phase I study, would be the goal of a Phase II study.

项目概要 在美国，产前酒精暴露是导致出生缺陷的主要可预防原因， 产生一系列神经、行为和身体异常，统称为 胎儿酒精谱系障碍（FASD）。早期干预和治疗计划已 已被证明可以减少一些长期不利影响，但这取决于确定 儿童面临胎儿受损的风险，而这种情况在大多数情况下未被发现。许多孩子受到影响 FASD 没有表现出与产前酒精相关的出生缺陷的明显身体迹象， 给及时、准确的诊断带来了挑战。迫切需要 开发可以检测整个过程中严重暴露于酒精的婴儿的生物标记物 怀孕期间，尤其是在怀孕的前三个月，此时胎儿的大脑最容易受到 致畸剂，预测那些有神经行为和发育风险的人 与 FASD 相关的残疾。产前酒精暴露已被证明会改变 DNA 已知在发育中发挥重要作用并有助于 胚胎发育异常，表明与酒精相关的 DNA 改变 从新生儿血斑样本中鉴定出的甲基化谱可用作酒精 新生儿的生物标志物。结合美国药物测试实验室拥有的技术 开发用于检测血液中的直接酒精生物标志物磷脂酰乙醇 (PEth) 筛查与产前酒精暴露相关的表观遗传变化提供了 检查酒精暴露发生的新生物标志物的创新方法 整个怀孕期间，这可能预示着胎儿的损伤。第一阶段的目标 该项目旨在确定利用新生儿血斑筛查酒精引起的酒精中毒的可行性 DNA 甲基化改变并确定这些表观遗传修饰是否与 PEth 的检测。差异甲基化候选区域的选择将是 通过新生儿血斑样本 DNA 的全基因组甲基化扫描确定 从已知在子宫内接触过酒精的婴儿身上收集，并将其与未接触过酒精的婴儿进行比较 暴露的控件。如果产前酒精暴露与一组定义的显着相关 差异甲基化DNA位点，使用表观遗传标记检测的可行性 新生儿面临胎儿损伤的风险已经确定，这些表观遗传模式可能 作为 FASD 的可能预测生物标志物进行进一步检查。发展与 实施定量 DNA 甲基化筛选测定，以分析 DNA 甲基化位点 在第一阶段研究中发现的差异甲基化将是第二阶段研究的目标。