Oxidant Stress and Gene Polymorphisms in Bronchopulmonary Dysplasia

描述(由申请人提供)：支气管肺发育不良(BPD)是最常见的婴幼儿慢性肺部疾病，与显著的发病率、死亡率和费用有关。其发病机制仍然知之甚少，疾病的预测因素仍有待确定。梅斯坦博士致力于阐明导致BPD的机制，以便制定预防策略以减少其发生率。她的短期目标是在王晓斌博士的主要指导下，研究BPD与生物标记物(8-异前列腺素和8-羟基脱氧鸟苷(8-OHdG))以及氧化应激途径中涉及的基因多态之间的流行病学关联。这一奖项将允许梅斯坦博士获得必要的技能，以发展她的研究项目，并成为一名独立的研究员。她的职业发展计划包括一项多学科的教学培训计划，以及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，如脐带血和尿8-异前列腺素和8-羟色胺，以及特定的基因多态性，可以独立或交互作用地影响BPD的发展。她提议的研究将使用两个出生中心的资源：波士顿医疗中心(BMC)出生队列由王博士及其同事于1998年建立，是美国正在进行的最大的出生队列之一；西北纪念医院(NMH)队列由Mestan博士于2006年在当地发起，并将在她的导师的指导下进一步发展。她将使用1,200名早产儿的1：2病例对照设计，调查以下具体目标：1)确定脐带血和尿液氧化应激生物标记物与BPD发生之间的关系；2)评估有希望的候选基因(GSTP1、SOD3)与BPD风险的遗传关联，并调整重要的临床变量、人群混合和多重测试。该项目完成后，梅斯坦博士将在生化分析和基因分型技术以及先进的统计和遗传分析方面获得基本经验，为未来BPD及其结果的研究设计和进行。 项目简介：在确定BPD的预测生化和遗传标记后，我们将能够更好地识别高危婴儿，提供更早和更有针对性的干预措施，并最终降低BPD的发生率和严重程度。反过来，这将改善BPD患者的长期结局，对他们的家庭产生积极影响，并将管理这种复杂疾病给社会带来的经济负担降至最低。

DESCRIPTION (provided by applicant): 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. Project Narrative: Upon the identification of predictive biochemical and genetic markers of BPD, we will be better able to identify high-risk infants, provide earlier and more targeted interventions, and ultimately reduce the incidence and severity of BPD. In turn, this will improve the long-term outcomes of BPD patients, positively impact their families, and minimize the financial burden to society in managing this complex disease.