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Impaired angiogenesis in preterm infants after maternal complications of pregnancy

母亲妊娠并发症后早产儿血管生成受损

基本信息

批准号：
9186561
负责人：
CHRISTOPHER D BAKER
金额：
$ 19.21万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9186561
关键词：
Adult Alveolar Animal Model Apoptotic Award Basic Science Biological Assay Biological Markers Biostatistical Methods Blood Circulation Blood Tests Blood Vessels Bronchopulmonary Dysplasia Cell Count Cell Separation Cell physiology Cells Cellular biology Child Childhood Chronic Chronic lung disease Clinical Clinical Oncology Supplement (K12)Clinical Research Colorado Complex Data Databases Development Development Plans Disease Echocardiography Educational workshop Emergency department visit Ensure Environment Epidemiology Fetal Growth Retardation Goals Growth Healthcare Human Hypoxemia Impairment In Vitro Infant Injury Institutes Italy K-Series Research Career Programs Lead Learning Letters Life Link Literature Longitudinal Studies Lung Lung diseases Maternal Complication of Pregnancy Mediating Mediation Mentored Patient-Oriented Research Career Development Award Mentors Mentorship Mothers National Heart, Lung, and Blood Institute Outcome Outpatients Oxidative Stress Participant Pathogenesis Phenotype Play Pre-Eclampsia Pregnancy Complications Premature Birth Premature Infant Prevention Public Health Schools Pulmonary Hypertension Pulmonology Quality of life Research Research Personnel Risk Risk Factors Scientist Severities Stem cells Structure Syndrome Testing Translating Translational Research Umbilical Cord Blood United States United States National Institutes of Health Universities Visit angiogenesis antenatal base blood vessel development career career development cohort cytokine epidemiology study experience follow-up health care service utilization hospital readmission improved insight interest intraamniotic infection maternal cigarette smoking medical schools multidisciplinary novel pediatric department peripheral blood premature preterm newborn professor public health relevance respiratory skills submicron success translational approach translational study

项目摘要

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.

描述（由申请人提供）：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），这是一种与严重呼吸系统并发症相关的慢性肺病，持续到成年。BPD是由肺血管和肺泡生长中断引起的。流行病学研究表明，母体妊娠并发症，如先兆子痫、绒毛膜炎和宫内生长受限（IUGR），会增加BPD的风险。然而，母体妊娠并发症导致更严重BPD的机制尚不清楚。我们推测母体妊娠并发症破坏了早产新生儿的血管生成，导致更严重的BPD。候选人：我是儿科系的一名助理教授，并获得了儿科肺部医学的认证。作为NIH K12奖获得者，我在内皮祖细胞（EPC）生物学方面进行了基础科学研究，并精通EPC分离和表征。我过去的研究表明，来自早产儿的EPCs是高度增殖的，并且特别容易受到氧化应激的影响。然后，我表明，脐带血内皮祖细胞减少早产儿谁后来发展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的流行病学风险因素与血管生成生物标志物联系起来，以提示BPD发病机制，并确定风险最大的早产儿。我已经描述了一个有重点的职业发展计划，使我能够独立进行临床转化研究。这个K23职业发展奖申请将提供三年的关键支持，使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.运用统计中介分析来检验我的假设。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，将有效地将肺血管发育的机械基础研究转化为关于支气管肺发育不良（BPD）发病机制和潜在治疗的新见解。在这个奖项期间的第二年，我将提交我的第一个R01申请关于血管生成生物标志物和儿童BPD的结果。研究：基于目前的文献和我们的初步数据，该建议的中心假设是，母体妊娠并发症改变了早产儿的血管生成生物标志物，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制生物标志物和BPD严重程度的纵向评估联系起来，在一个特征良好的母亲及其早产儿队列中。为了检验上述假设，我们提出了以下具体目标：目的1：确定是否特定的母体妊娠并发症与脐带血血管生成生物标志物的改变。我们将检验以下假设：妊娠的产前并发症会降低脐带血血管生成生物标志物（ECFC，CPC：非CPC，血管生成细胞因子），在体外破坏ECFC功能，并增加内皮微粒（血管损伤的独立标志物），提供进一步的证据表明发生BPD的早产儿肺部血管生成被破坏。目的2：确定外周血血管生成生物标志物是否与出生后第一年内BPD的严重程度相关。我们将检验以下假设：在生命早期，通过超声心动图检查，患有重度BPD伴慢性低氧血症、再次入院/艾德访视和肺动脉高压的早产儿循环ECFC减少，ECFC功能受损。目标3：进行统计中介分析，以确定BPD是否与母体妊娠并发症相关，通过血管生成生物标志物提示的血管生成受损。我们将利用新的生物统计学方法来检验这一假设，即母体妊娠并发症与BPD通过破坏早产儿血管生成有关。这个研究计划代表了我的研究合乎逻辑的下一步。当我进行门诊随访时，我将与研究参与者进行直接互动环境：正如本提案和支持信中所述，我得到了知名研究人员（来自大学儿科系）的强有力的多学科指导。科罗拉多医学院、科罗拉多公共卫生学院和科罗拉多临床转化科学研究所）。我的导师团队在临床转化研究方面拥有丰富的经验，并且在之前的成功导师方面有着良好的记录。这种环境使我能够发展所需的技能，进行血管生成检测，开发临床数据库，并将确保这一建议的成功，为我的独立研究做好准备。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hospital to Home: A Quality Improvement Initiative to Implement High-fidelity Simulation Training for Caregivers of Children Requiring Long-term Mechanical Ventilation.

DOI：
10.1016/j.pedn.2017.08.028
发表时间：
2018-01
期刊：
Journal of pediatric nursing
影响因子：
0
作者：
Thrasher J;Baker J;Ventre KM;Martin SE;Dawson J;Cox R;Moore HM;Brethouwer S;Sables-Baus S;Baker CD
通讯作者：
Baker CD

Point Prevalence, Clinical Characteristics, and Treatment Variation for Infants with Severe Bronchopulmonary Dysplasia.