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）是早产儿呼吸衰竭机械通气和氧疗后的慢性肺部疾病。BPD是一种复杂的疾病，其特征在于畸形的肺血管生长和肺泡化减少，遗传和环境因素之间的相互作用促成了其病理生物学。临床研究强烈支持BPD的遗传基础，但导致BPD发病机制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暗示了血管生成受损在BPD发病机制中的关键作用。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存活因子，可刺激肺血管生成并维持血管功能。VEGF通过上调内皮型一氧化氮合酶（eNOS）刺激血管生成，eNOS增加一氧化氮（NO）的产生。在几个物种中的BPD的实验模型已经显示，由于高氧化应激而导致的VEGF信号传导受损、eNOS基因表达降低和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表达减少。在BPD动物模型中，吸入NO治疗可增强肺泡和血管生长并降低肺血管阻力，进一步表明NO产生或生物利用度降低可能导致早产儿慢性肺病。另外的实验室研究已经进一步证明了VEGF-NO信号传导和其他血管生成分子（包括血管生成素-Tie 2系统、内皮素-1和前列环素）以及肺生长和结构中的循环内皮祖细胞（EPC）之间的关键相互作用。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传导的遗传变异，包括循环EPCs，增加了早产儿对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描述BPD的临床表型和亚型。使用定量表型，我们将采用基于人群和基于家庭的联合关联检验（包括从母亲、父亲和受影响儿童三人组收集DNA），利用来自科罗拉多大学和印第安纳州大学早产儿前瞻性研究受试者的DNA，这些受试者具有发生BPD的高风险。项目叙述：支气管肺发育不良（BPD）是早产儿呼吸衰竭机械通气和氧疗后发生的慢性肺部疾病。BPD是一种复杂的疾病，其特征在于畸形的肺血管生长和肺泡化减少，遗传和环境因素之间的相互作用促成了其病理生物学。临床研究强烈支持BPD的遗传基础，但导致BPD发病机制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暗示了血管生成受损在BPD发病机制中的关键作用。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存活因子，可刺激肺血管生成并维持血管功能。VEGF通过上调内皮型一氧化氮合酶（eNOS）刺激血管生成，eNOS增加一氧化氮（NO）的产生。在几个物种中的BPD的实验模型已经显示，由于高氧化应激而导致的VEGF信号传导受损、eNOS基因表达降低和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表达减少。在BPD动物模型中，吸入NO治疗可增强肺泡和血管生长并降低肺血管阻力，进一步表明NO产生或生物利用度降低可能导致早产儿慢性肺病。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（包括血管生成素-Tie 2系统、内皮素-1和前列环素）以及肺生长和结构中循环内皮祖细胞（EPCs）之间的关键相互作用。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传导的遗传变异，包括循环EPCs，增加了早产儿对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描述BPD的临床表型和亚型。使用定量表型，我们将采用基于人群和基于家庭的联合关联检验（包括从母亲、父亲和受影响儿童三人组收集DNA），利用来自科罗拉多大学和印第安纳州大学早产儿前瞻性研究受试者的DNA，这些受试者具有发生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.