Impaired angiogenesis in preterm infants after maternal complications of pregnancy

 描述(申请人提供)：临床问题：在美国出生的所有儿童中有10%患有早产，其中10%患有支气管肺发育不良(BPD)，这是一种与严重的呼吸道并发症相关的慢性肺部疾病，一直持续到成年。BPD是由于肺血管和肺泡生长受阻所致。流行病学研究表明，妊娠的母体并发症，如先兆子痫、绒毛膜羊膜炎和宫内生长受限(IUGR)，增加了BPD的风险。然而，母体妊娠并发症导致更严重的BPD的机制尚不清楚。我们推测，母体妊娠并发症扰乱了早产儿的血管生成，导致了更严重的BPD。应聘者：我是儿科助理教授，拥有儿科肺部医学证书。作为NIH K12奖获得者，我从事内皮祖细胞生物学的基础科学研究，并精通内皮祖细胞的分离和鉴定。我过去的研究表明，早产儿的内皮祖细胞高度增殖，特别容易受到氧化应激的影响。然后，我发现早产儿脐血内皮祖细胞减少，这些早产儿后来患上了BPD。这些发现激发了我目前的研究兴趣，利用先进的生物统计学方法将BPD的流行病学危险因素与血管生成生物标记物联系起来，以建议BPD的发病机制，并确定哪些早产儿风险最高。我已经描述了一个有重点的职业发展计划，它将使我能够独立进行临床-翻译研究。这份K23职业发展奖申请书将提供三年的关键支持，以便我可以实现我的短期目标：1.学习最先进的定量应用生物统计学方法。2.运用统计中介分析对我的具体假设进行检验。这将使我能够实现我的长期职业目标，成为一名独立的临床科学家，有效地将肺血管发育的机械性基础研究转化为对支气管肺发育不良(BPD)的发病机制和潜在治疗的新见解。在获奖期的第二年，我将提交我的第一份R01申请，涉及血管生成生物标记物和儿童BPD结果。研究：基于目前的文献和我们的初步数据，这一建议的中心假设是孕妇妊娠并发症改变了早产儿的血管生成生物标记物，表明EPC介导的血管生成中断导致严重的BPD。在这项研究中，我们将利用一种综合的翻译方法，将BPD的流行病学危险因素与新的机械性生物标记物联系起来，并在具有良好特征的母亲及其早产儿队列中对BPD严重程度进行纵向评估。为了验证上述假设，我们提出了以下具体目标：目的1：确定特定的孕妇妊娠并发症是否与脐血血管生成生物标志物的改变有关。我们将检验这一假说，即妊娠并发症会降低脐血血管生成生物标志物(ECFC，CPC：非CPC，血管生成细胞因子)，破坏ECFC的体外功能，增加血管损伤的独立标志物内皮微粒，进一步提供BPD早产儿肺血管生成中断的证据。目的2：确定外周血血管生成生物标志物是否与出生第一年的BPD严重程度相关。我们将通过超声心动图对早产儿循环ECFC减少和ECFC功能紊乱的假说进行验证，这些早产儿发展为严重的BPD伴慢性低氧血症、再入院/急诊和早期肺动脉高压。目的：进行统计学中介分析，以确定BPD是否通过血管生成生物标记物提示的血管生成受损与母体妊娠并发症有关。我们将利用新的生物统计学方法来检验这一假设，即孕妇的妊娠并发症与早产儿血管生成障碍与BPD有关。这项研究计划代表了我研究的合乎逻辑的下一步。当我进行门诊随访时，我将与研究参与者直接互动：如本提案和支持信中所述，我得到了成熟研究人员(来自科罗拉多大学医学院儿科系、科罗拉多公共卫生学院和科罗拉多临床转化科学研究所)的强大的多学科指导。我的指导团队在临床翻译研究方面有丰富的经验，在之前成功的指导方面有很好的记录。这种环境使我能够发展进行血管生成分析所需的技能，开发临床数据库，并将确保这一提案的成功，为我的独立研究做好准备。

 DESCRIPTION (provided by applicant): The Clinical Problem: 10% of all children born in the United States suffer from preterm birth and 10% of these develop bronchopulmonary dysplasia (BPD), the chronic lung disease associated with significant respiratory complications that continue into adulthood. BPD results from a disruption in pulmonary vascular and alveolar growth. Epidemiological studies have shown that maternal complications of pregnancy, such as preeclampsia, chorioamnionitis, and intrauterine growth restriction (IUGR), increase the risk for BPD. However, the mechanisms through which maternal complications of pregnancy lead to more severe BPD are unclear. We speculate that maternal complications of pregnancy disrupt angiogenesis in preterm newborns resulting in more severe BPD. The Candidate: I am an assistant professor in the Department of Pediatrics and board certified in pediatric pulmonary medicine. As an NIH K12 award recipient, I performed basic science research in endothelial progenitor cell (EPC) biology and became proficient in EPC isolation and characterization. My past studies demonstrated that EPCs from preterm infants are highly proliferative and uniquely susceptible to oxidative stress. I then showed that cord blood EPCs are decreased in preterm infants who later develop BPD. These findings inspired my current research interest, to utilize advanced biostatistical methods to link epidemiological risk factors for BPD with angiogenic biomarkers to suggest mechanisms of BPD pathogenesis and identify those preterm infants at greatest risk. I have described a focused career development plan that will enable me to independently conduct clinical-translational research. This K23 Career Development Award application will provide three years of critical support so that I may achieve my short-term goals: 1. To learn state-of-the-art quantitative applied biostatistical methods. 2. To apply statistical mediation analysis to test my specific hypothesis. This will enable me to attain my long-term career goal of becoming an independent clinician scientist who will effectively translate mechanistic basic studies in pulmonary vascular development into new insights regarding the pathogenesis and potential treatment of bronchopulmonary dysplasia (BPD). During the second year of this award period, I will submit my first R01 application concerning angiogenic biomarkers and BPD outcomes in childhood. The Research: Based on the current literature and our preliminary data, the central hypothesis to this proposal is that maternal complications of pregnancy alter angiogenic biomarkers in preterm infants suggesting a disruption in EPC- mediated angiogenesis that results in severe BPD. In this study, we will utilize an integrated translational approach to connect epidemiological risk factors for BPD with novel mechanistic biomarkers and longitudinal assessments of BPD severity in a well-characterized cohort of mothers and their preterm newborns. To test the hypothesis above, we propose the following specific aims: Aim 1: To determine whether specific maternal complications of pregnancy are associated with altered cord blood angiogenic biomarkers. We will test the hypothesis that antenatal complications of pregnancy decrease cord blood angiogenic biomarkers (ECFCs, CPC:non-CPC, angiogenic cytokines), disrupt ECFC function in vitro, and increase endothelial microparticles, an independent marker of vascular injury, providing further evidence that angiogenesis is disrupted in the lungs of preterm infants who develop BPD. Aim 2: To determine whether peripheral blood angiogenic biomarkers are associated with BPD severity during the first year of life. We will test the hypothesis that circulating ECFCs are decreased and ECFC function is disrupted in preterm infants who develop severe BPD with chronic hypoxemia, hospital readmissions/ED visits, and pulmonary hypertension by echocardiography during early life. Aim 3: To perform statistical mediation analysis to determine whether BPD is associated with maternal complications of pregnancy through impaired angiogenesis as suggested by angiogenic biomarkers. We will utilize novel biostatistical methods to test the hypothesis that maternal complications of pregnancy are associated with BPD through disrupted angiogenesis in preterm infants. This research plan represents the logical next step for my research. As I perform the outpatient follow-up visits, I will have direct interaction with the study participants The Environment: As described in this proposal and the letters of support, I have strong multidisciplinary mentorship by established investigators (from the Departments of Pediatrics in the University of Colorado School of Medicine, the Colorado School of Public Health, and the Colorado Clinical Translational Sciences Institute). My mentoring team has extensive experience in clinical translational research and a strong track record of prior successful mentorship. This environment has enabled me to develop the skills needed to perform the angiogenic assays, to develop a clinical database, and will ensure the success of this proposal to prepare me for independent research.