PILOT STUDY OF IMPAIRED ANGIOGENIC SIGNALING IN BRONCHOPULMONARY DYSPLASIA

支气管肺发育不良血管生成信号传导受损的试点研究

• 批准号: 7605138
• 负责人: PETER M MOURANI
• 金额: $ 3.73万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7605138
• 关键词: Affect; Alveolar; Animal Model; Biological Availability; Biological Markers; Blood Vessels; Bronchopulmonary Dysplasia; Child; Chronic lung disease; Clinical Research; Collection; Colorado; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA; Data; Development; Disease; Echocardiography; Endothelial Cells; Endothelin-1; Enrollment; Environmental Risk Factor; Epoprostenol; Experimental Models; Family; Fathers; Funding; Gene Expression; Generations; Genes; Genetic; Genetic Variation; Grant; Growth; Incidence; Infant; Inflammation; Institution; Laboratory Study; Lung; Mechanical ventilation; Mitogens; Mothers; Newborn Infant; Nitric Oxide; Nitric Oxide Pathway; Observational Study; Oxidants; Oxygen; Oxygen Therapy Care; Pathogenesis; Pilot Projects; Population; Predisposition; Production; Prostaglandins I; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary function tests; Research; Research Personnel; Resources; Respiratory Failure; Risk; Role; Severities; Signal Transduction; Source; Stress; Structure; Superoxide Dismutase; Superoxides; System; Testing; United States National Institutes of Health; Universities; Up-Regulation; Variant; Vascular Diseases; Vascular Endothelial Growth Factors; angiogenesis; base; clinical phenotype; genetic risk factor; human NOS3 protein; inhaled nitric oxide; prospective; trend

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Bronchopulmonary dysplasia (BPD) is the chronic lung disease that follows mechanical ventilation and oxygen therapy for respiratory failure in premature newborns. Characterized by dysmorphic lung vascular growth and decreased alveolarization, BPD is a complex disease with interactions between genetic and environmental factors contributing to its pathobiology. Clinical studies strongly support a genetic basis for BPD, but genetic risk factors that contribute to the pathogenesis or severity of BPD are unknown. Over the past several years, our lab and others have implicated a critical role for impaired angiogenesis in the pathogenesis of BPD. Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and survival factor that stimulates lung angiogenesis and maintains vascular function. VEGF stimulates angiogenesis through upregulation of endothelial nitric oxide synthase (eNOS), which increases nitric oxide (NO) production. Experimental models of BPD in several species have shown that impaired VEGF signaling, decreased eNOS gene expression, and decreased NO bioavailability due to high oxidant stress (due to increased generation of superoxide from inflammation and decreased scavenging by superoxide dismutase (SOD)) increase susceptibility of the developing lung for pulmonary hypertension, impaired angiogenesis and reduced alveolarization. Clinically, reduced lung VEGF expression has been found in infants dying with BPD and pulmonary vascular disease. Inhaled NO therapy enhances alveolar and vascular growth and lowers pulmonary vascular resistance in animal models of BPD, further suggesting that reduced NO production or bioavailability may contribute to chronic lung disease in premature newborns. Additional laboratory studies have further demonstrated critical interactions between VEGF-NO signaling and other angiogenic molecules, including the angiopoietin-Tie 2 system, endothelin-1, and prostacyclin, in lung growth and structure. Based on these findings, we hypothesize that early pulmonary vascular disease contributes to the incidence and severity of BPD, and that genetic variations that impair the VEGF-NO pathways and angiogenic signaling increase the susceptibility of premature newborns for the development of BPD. In these pilot studies, we will carefully characterize the clinical phenotype and subtypes of BPD through precise determination of oxygen requirement, early morbisities and serial echocardiograms and infant pulmonary function tests. Using the quatitative pehenotype, we will identify early angiogenic biomarkers and variations in angiogenic genes that are associated with BPD. For the genetic studies, we will employ a combined population based and family based association test (involving the collection of DNA from mother, father, and affected child trios), utilizing DNA from subjects enrolled into a prospective observational study of premature newborns at the University of Colorado who are at high risk for developing BPD and pulmonary hypertension. This pilot study is intended to determine the feasibility of such a project and to obtain preliminary data and identify trends in both biomarker and genetic data in order to narrow the scope and adequately power a larger more complete study evaluating these study questions. This pilot study is structured in such a way that these data can also be used by the subsequent larger study.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 支气管肺发育不良（BPD）是一种慢性肺部疾病，遵循机械通气和氧气治疗的早产新生儿的呼吸衰竭。 BPD以畸形肺血管生长和肺泡化降低为特征，是一种复杂的疾病，遗传因素与环境因素之间的相互作用有助于其病理生物学。临床研究强烈支持BPD的遗传基础，但是造成BPD发病机理或严重程度的遗传危险因素尚不清楚。在过去的几年中，我们的实验室和其他实验室在BPD的发病机理中暗示了血管生成受损的关键作用。血管内皮生长因子（VEGF）是一种有效的内皮细胞有丝分裂原和生存因子，可刺激肺血管生成并保持血管功能。 VEGF通过上调内皮一氧化氮合酶（ENOS）刺激血管生成，从而增加一氧化氮（NO）产生。 BPD在几种物种中的实验模型表明，VEGF信号传导受损，eNOS基因表达降低以及由于高氧化剂应激而没有降低生物利用度（由于炎症中超氧化物产生的产生增加，并通过上氧化物歧化酶（SOD）（SOD）降低了肺动脉症（SOD）的清除降低）增加了发育肺部对肺动脉抗体的炎症的敏感性，使肺动脉吻合式高压剂量造成的阳性良好，并降低。在临床上，在伴有BPD和肺血管疾病的婴儿中发现肺VEGF表达降低。吸入的无治疗可增强肺泡和血管生长，并降低BPD动物模型中的肺血管耐药性，进一步表明，没有生产或生物利用性降低可能导致早产新生儿的慢性肺病。其他实验室研究进一步证明了VEGF-NO信号传导与其他血管生成分子之间的关键相互作用，包括血管生成素2系统，内皮素-1和前列环素在肺部生长和结构中。基于这些发现，我们假设早期肺血管疾病有助于BPD的发病率和严重程度，并且损害VEGF-NO途径和血管生成信号的遗传变异增加了早产新生儿对BPD发展的敏感性。在这些初步研究中，我们将通过精确确定氧需求，早期病态和串行超声心动图和婴儿肺功能测试来仔细表征BPD的临床表型和亚型。使用优质的Pehenotype，我们将确定与BPD相关的血管生成基因的早期血管生成生物标志物和变化。对于遗传研究，我们将采用基于人群和家庭的关联测试（涉及母亲，父亲和受影响的儿童三重奏的DNA），利用来自科罗拉多州大学早期新生儿的前瞻性观察研究的受试者的DNA，这些研究对BPD和肺动脉高压的高风险高风险。这项试点研究旨在确定此类项目的可行性，并获得初步数据并确定生物标志物和遗传数据的趋势，以缩小范围并充分为评估这些研究问题的更完整的研究提供更大的更完整的研究。这项试验研究的结构是使这些数据也可以通过随后的大型研究来使用。