Oxidant Stress and Gene Polymorphisms in Bronchopulmonary Dysplasia

支气管肺发育不良（BPD）是婴儿期最常见的慢性肺部疾病，与显著的发病率、死亡率和成本相关。其发病机制仍然知之甚少，疾病的预测因素仍有待确定。Mestan博士致力于阐明导致BPD的机制，以便制定预防策略以降低其发病率。她的短期目标是研究BPD与生物标志物（8-异前列烷和8-羟基脱氧鸟苷（8- OHdG））和氧化应激途径中涉及的基因多态性的流行病学关联，在Xiaobin Wang博士的主要指导下。该奖项将使Mestan博士获得必要的技能，以发展她的研究计划，并成为一名独立的调查员。她的职业发展计划包括教学培训的多学科计划和密切指导的分子和遗传流行病学研究经验。她的中心假设是，围产期和出生后的氧化应激，如测量脐带血和尿8-异前列腺素和8-OHdG，和特定的基因多态性可以独立或交互影响BPD的发展。她提出的研究将利用两个出生中心的资源：波士顿医学中心（BMC）出生队列由王博士及其同事于1998年建立，是美国最大的正在进行的出生队列之一;西北纪念医院（NMH）队列是由Mestan博士于2006年在当地发起的，并将在她的导师的指导下进一步发展。使用1：2的病例对照设计的1,200名早产儿，她将调查以下具体目的：1）确定脐带血和尿氧化应激生物标志物和BPD的发展之间的关系;和2）评估有希望的候选基因（GST 1，SOD 3）与BPD的风险的遗传关联，调整重要的临床变量，人口混合，和多重测试。完成该项目后，Mestan博士将获得生化检测和基因分型技术以及先进的统计和遗传分析方面的基本经验，用于设计和进行未来的BPD及其结果研究。

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease of infancy and is associated with significant morbidity, mortality and cost. Its pathogenesis remains poorly understood and predictors of the disease remain to be identified. Dr. Mestan is committed to elucidating the mechanisms that lead to BPD so that preventive strategies could be developed to decrease its incidence. Her short term goal is to investigate the epidemiologic associations of BPD with biomarkers (8-isoprostane and 8-hydroxydeoxyguanosine (8- OHdG)) and gene polymorphisms implicated in pathways of oxidant stress, under the primary mentorship of Dr. Xiaobin Wang. This award would allow Dr. Mestan to gain the necessary skills to develop her research program and become an independent investigator. Her career development plan involves a multi-disciplinary program of didactic training and closely mentored molecular and genetic epidemiological research experiences. Her central hypothesis is that peripartum and postnatal oxidant stress, as measured by cord blood and urinary 8-isoprostane and 8-OHdG, and specific gene polymorphisms can independently or interactively affect the development of BPD. Her proposed study will employ the resources of two birth centers: The Boston Medical Center (BMC) birth cohort was established by Dr. Wang and colleagues in 1998, and is one of the largest ongoing birth cohorts in the U.S.; The Northwestern Memorial Hospital (NMH) cohort was initiated locally by Dr. Mestan in 2006, and will be developed further under the guidance of her mentors. Using a 1:2 case-control design of 1,200 preterm infants, she will investigate the following Specific Aims: 1) To identify relationships between cord blood and urinary biomarkers of oxidant stress and the development of BPD; and 2) To assess genetic associations of promising candidate genes (GSTP1, SOD3) with the risk of BPD, with adjustment for important clinical variables, population admixture, and multiple testing. Upon completion of this project, Dr. Mestan will have acquired essential experience in biochemical assay and genotyping techniques, and advanced statistical and genetic analyses, for the design and conduction of future studies of BPD and its outcomes.