The Effects of Fatty Acid Ethyl Esters on the Developing Lung

描述（由申请人提供）：尽管对酒精的有害影响进行了教育，但怀孕期间使用酒精仍然是一个问题，包括神经发育迟缓和感染风险增加，对未出生的孩子。这一研究领域的障碍之一是母亲由于担心后果和社会耻辱而对怀孕期间饮酒的情况报告不足。直到最近，产前接触酒精的明确生物标志物还没有建立。目前正在进行的研究表明，在胎粪和头发样本中检测到的酒精代谢的非氧化副产物脂肪酸乙酯（FAEE）是足月新生儿宫内酒精暴露的有用指标。尽管如此，未在早产儿中进行研究。因此，关于产前酒精暴露对早产儿，特别是早产儿肺发育的影响的研究仍然非常有限。本提案中概述的研究将确定产前酒精暴露是否会增加早产豚鼠动物模型肺中细胞毒性脂肪酸乙酯（FAEE）的蓄积（目的1）。然后，我们将检查这些脂肪酸乙酯的积累是否影响肺部免疫细胞，肺泡巨噬细胞的功能，肺泡巨噬细胞是肺部感染的第一道防线（目的2）。将通过对子宫内暴露于ETOH的早产豚鼠和对照动物进行各种实验来检查这些假设。我们将评估肺组织和巨噬细胞中FAEE的存在，确定这些FAEE是否影响肺巨噬细胞的功能或活力，以及某些FAEE是否比其他FAEE更有害。这些结果可以阐明产前酒精暴露如何增加早产儿感染和肺损伤风险的新机制。这些信息最终将有助于确定可能的治疗干预措施，以保护暴露的早产儿免受呼吸道感染和感染介导的发病率和死亡率。 利用这个NRSA赠款的支持，完善的研究导师的指导，以及埃默里大学和埃默里酒精和肺生物学中心提供的机会和资源，即将到来的一年博士后培训将用于扩大我的研究设计/赠款和手稿写作的知识，完善调查技能，并在实验室学习新技术。这段时间也将允许我的研究和临床职业生涯的整合，并有机会获得数据，这些数据将用于申请长期的NIH赞助的职业发展资金。今年将为我的长期目标做好准备，成为新生儿研究领域一名成功的独立学术研究人员。 公共卫生相关性：怀孕期间饮酒导致很大比例的早产儿和足月新生儿出生前接触酒精，这仍然是一个问题，尽管公众宣布酒精对未出生的孩子的有害影响。尽管如此，产前酒精暴露对早产新生儿的影响的研究非常有限，因此，为了解决这个问题，本提案将确定产前酒精暴露是否会增加早产豚鼠动物模型肺中细胞毒性脂肪酸乙酯（FAEE）的积累，以及这些FAEE是否会影响肺泡巨噬细胞功能。这些结果可以阐明产前酒精暴露是否会增加早产儿已经增加的感染和肺损伤风险。

DESCRIPTION (provided by applicant): Alcohol use during pregnancy remains a problem despite education regarding the detrimental effects of alcohol, including neurodevelopmental delays and increased risk for infection, on the unborn child. One of the obstacles in this field of research is the under-reporting, by mothers, of alcohol use during pregnancy due to the fear of repercussions and social stigma. Until recently, a clear biomarker of prenatal exposure to alcohol had not been established. Ongoing studies now show that Fatty Acid Ethyl Esters (FAEE), non-oxidative by- products of alcohol metabolism, detected in meconium and hair samples are useful indicators of in utero alcohol exposure in full term newborns. Despite this, studies were not carried out in preterm newborns. Therefore, there is still very limited research on the effects of prenatal alcohol exposure on the premature newborn and specifically the premature developing lung. The studies outlined in this proposal will determine if prenatal alcohol exposure increases the accumulation of cytotoxic Fatty Acid Ethyl Esters (FAEE) in the lungs of our preterm guinea pig animal model (Aim 1). Then, we will examine whether the accumulation of these Fatty Acid Ethyl Esters affects the function of the lung's immune cells, alveolar macrophages, which are the first line of defense against infection in the lung (Aim 2). These hypotheses will be examined by performing various experiments on in utero ETOH-exposed preterm guinea pigs and control animals. We will evaluate the presence of FAEE in the lung tissue and macrophages, determine whether these FAEE affect lung macrophages' function or viability, and whether certain FAEE are more harmful than others. These results could elucidate a novel mechanism of how prenatal alcohol exposure increases the premature newborn's risk for infection and lung injury. This information will eventually aid in the identification of possible therapeutic interventions to protect the exposed premature newborn from respiratory infections and infection-mediated morbidity and mortality. Using the support from this NRSA grant, the guidance of well established research mentors, and the opportunities and resources available at Emory University and the Emory Alcohol and Lung Biology Center, the upcoming year of post-doctoral training will be used to expand my knowledge of research design/grant and manuscript writing, refine investigative skills, and learn new techniques in the lab. This time will also allow for the integration of my research and clinical career and the opportunity to obtain data which will be utilized to apply for long-term, NIH sponsored career development funding. This year will prepare me for my long-term goal of becoming a successful independent academic researcher in the field of neonatal research. PUBLIC HEALTH RELEVANCE: Alcohol use during pregnancy, which results in a significant proportion of both premature and term newborn infants born with prenatal alcohol-exposure, remains a problem despite public announcements regarding the detrimental effects of alcohol on the unborn child. Despite this, there is very limited research on the effects of prenatal alcohol exposure on the premature newborn so, in an effort to address this issue, this proposal will determine if prenatal alcohol exposure increases the accumulation of cytotoxic Fatty Acid Ethyl Esters (FAEE) in the lungs of our preterm guinea pig animal model and whether these FAEE affect alveolar macrophage function. These results could elucidate whether prenatal alcohol exposure adds to the premature newborn's already increased risk for infection and lung injury.