Genetic Basis for Impaired Angiogenic Signaling in BPD

描述（由申请人提供）：支气管肺发育不良（BPD）是早产儿呼吸衰竭后机械通气和氧气治疗的慢性肺部疾病。BPD是一种复杂的疾病，其特征是肺血管生长畸形和肺泡化减少，遗传和环境因素相互作用导致其病理生物学。临床研究强烈支持BPD的遗传基础，但导致BPD发病或严重程度的遗传风险因素尚不清楚。在过去的几年里，我们的实验室和其他实验室已经发现血管生成受损在BPD的发病机制中起着关键作用。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，刺激肺血管生成和维持血管功能。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）的产生。一些物种的BPD实验模型表明，由于高氧化应激，VEGF信号受损，eNOS基因表达降低，NO生物利用度降低，增加了发育中的肺对肺动脉高压的易感性，血管生成受损和肺泡化减少。临床上，在死于BPD和肺血管疾病的婴儿中发现肺VEGF表达降低。在BPD动物模型中，吸入NO治疗可促进肺泡和血管生长，降低肺血管阻力，进一步表明NO生成或生物利用度降低可能与早产儿慢性肺部疾病有关。其他实验室研究进一步证明了VEGF-NO信号与其他血管生成分子（包括血管生成素- tie - 2系统、内皮素-1和前列环素）和循环内皮祖细胞（EPCs）在肺生长和结构中的关键相互作用。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通路和血管生成信号的遗传变异，包括循环EPCs，增加了早产儿BPD发展的易感性。在这些研究中，我们将通过精确测定需氧量、早期发病率和连续超声心动图来仔细表征BPD的临床表型和亚型。使用定量表型，我们将采用基于群体和基于家庭的联合关联测试（包括收集母亲，父亲和受影响的孩子三人的DNA），使用来自科罗拉多大学和印第安纳大学早产儿前瞻性研究的DNA，这些研究对象患有BPD的高风险。项目简介：支气管肺发育不良（BPD）是早产儿呼吸衰竭后机械通气和氧气治疗的慢性肺部疾病。BPD是一种复杂的疾病，其特征是肺血管生长畸形和肺泡化减少，遗传和环境因素相互作用导致其病理生物学。临床研究强烈支持BPD的遗传基础，但导致BPD发病或严重程度的遗传风险因素尚不清楚。在过去的几年里，我们的实验室和其他实验室已经发现血管生成受损在BPD的发病机制中起着关键作用。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，刺激肺血管生成和维持血管功能。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）的产生。一些物种的BPD实验模型表明，由于高氧化应激，VEGF信号受损，eNOS基因表达降低，NO生物利用度降低，增加了发育中的肺对肺动脉高压的易感性，血管生成受损和肺泡化减少。临床上，在死于BPD和肺血管疾病的婴儿中发现肺VEGF表达降低。在BPD动物模型中，吸入NO治疗可促进肺泡和血管生长，降低肺血管阻力，进一步表明NO生成或生物利用度降低可能与早产儿慢性肺部疾病有关。其他实验室研究进一步证明了VEGF-NO信号与其他血管生成分子（包括血管生成素- tie - 2系统、内皮素-1和前列环素）和循环内皮祖细胞（EPCs）在肺生长和结构中的关键相互作用。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通路和血管生成信号的遗传变异，包括循环EPCs，增加了早产儿BPD发展的易感性。在这些研究中，我们将通过精确测定需氧量、早期发病率和连续超声心动图来仔细表征BPD的临床表型和亚型。使用定量表型，我们将采用基于群体和基于家庭的联合关联测试（包括收集母亲，父亲和受影响的孩子三人的DNA），使用来自科罗拉多大学和印第安纳大学早产儿前瞻性研究的DNA，这些研究对象患有BPD的高风险。

DESCRIPTION (provided by applicant): 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 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, and circulating endothelial progenitor cells (EPCs) 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, including circulating EPCs, increase the susceptibility of premature newborns for the development of BPD. In these studies, we will carefully characterize the clinical phenotype and subtypes of BPD through precise determination of oxygen requirement, early morbidities and serial echocardiograms. Using the quantitative phenotype, 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 study of premature newborns at the University of Colorado and Indiana University who are at high risk for developing BPD. Project Narrative: 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 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, and circulating endothelial progenitor cells (EPCs) 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, including circulating EPCs, increase the susceptibility of premature newborns for the development of BPD. In these studies, we will carefully characterize the clinical phenotype and subtypes of BPD through precise determination of oxygen requirement, early morbidities and serial echocardiograms. Using the quantitative phenotype, 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 study of premature newborns at the University of Colorado and Indiana University who are at high risk for developing BPD.