Genetic Basis for Impaired Angiogenic Signaling in BPD

描述(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疗后的慢性肺部疾病。以肺血管畸形生长和肺泡化减少为特征的BPD是一种复杂的疾病，其发病机制与遗传和环境因素相互作用。临床研究强烈支持BPD的遗传学基础，但导致BPD发病或严重程度的遗传危险因素尚不清楚。在过去的几年里，我们的实验室和其他实验室已经证实血管生成受损在BPD的发病机制中起着关键作用。血管内皮生长因子(VEGF)是一种强大的内皮细胞有丝分裂原和生存因子，能刺激肺血管生成，维持血管功能。血管内皮生长因子通过上调内皮型一氧化氮合酶(ENOS)促进血管生成，从而增加一氧化氮(NO)的产生。多个物种的BPD实验模型表明，由于高氧化应激导致血管内皮生长因子信号转导受损，eNOS基因表达减少，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，阻碍了血管生成，减少了肺泡化。临床上，在死于BPD和肺血管疾病的婴儿中发现肺血管内皮生长因子表达减少。吸入NO治疗促进了BPD动物模型的肺泡和血管生长并降低了肺血管阻力，进一步表明NO产生或生物利用度的减少可能导致早产儿慢性肺部疾病。更多的实验室研究进一步证明了VEGF-NO信号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-Tie-2系统、内皮素-1和前列环素，以及循环内皮祖细胞(EPC)在肺生长和结构中的作用。基于这些发现，我们假设早期肺血管疾病与BPD的发生和严重程度有关，并且损害VEGF-NO通路和血管生成信号(包括循环内皮祖细胞)的基因变异增加了早产儿发生BPD的易感性。在这些研究中，我们将通过精确的需氧量、早期发病率和系列超声心动图来仔细描述BPD的临床表型和亚型。使用数量表型，我们将采用基于人群和基于家庭的联合测试(包括从母亲、父亲和受影响的儿童三人组收集DNA)，利用来自科罗拉多大学和印第安纳大学早产儿的DNA，这些受试者是在科罗拉多大学和印第安纳大学进行的一项早产儿的前瞻性研究，这些早产儿是BPD的高危人群。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疗后的一种慢性肺部疾病。以肺血管畸形生长和肺泡化减少为特征的BPD是一种复杂的疾病，其发病机制与遗传和环境因素相互作用。临床研究强烈支持BPD的遗传学基础，但导致BPD发病或严重程度的遗传危险因素尚不清楚。在过去的几年里，我们的实验室和其他实验室已经证实血管生成受损在BPD的发病机制中起着关键作用。血管内皮生长因子(VEGF)是一种强大的内皮细胞有丝分裂原和生存因子，能刺激肺血管生成，维持血管功能。血管内皮生长因子通过上调内皮型一氧化氮合酶(ENOS)促进血管生成，从而增加一氧化氮(NO)的产生。多个物种的BPD实验模型表明，由于高氧化应激导致血管内皮生长因子信号转导受损，eNOS基因表达减少，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，阻碍了血管生成，减少了肺泡化。临床上，在死于BPD和肺血管疾病的婴儿中发现肺血管内皮生长因子表达减少。吸入NO治疗促进了BPD动物模型的肺泡和血管生长并降低了肺血管阻力，进一步表明NO产生或生物利用度的减少可能导致早产儿慢性肺部疾病。更多的实验室研究进一步证明了VEGF-NO信号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-Tie-2系统、内皮素-1和前列环素，以及循环内皮祖细胞(EPC)在肺生长和结构中的作用。基于这些发现，我们假设早期肺血管疾病与BPD的发生和严重程度有关，并且损害VEGF-NO通路和血管生成信号(包括循环内皮祖细胞)的基因变异增加了早产儿发生BPD的易感性。在这些研究中，我们将通过精确的需氧量、早期发病率和系列超声心动图来仔细描述BPD的临床表型和亚型。使用数量表型，我们将采用基于人群和基于家庭的联合测试(包括从母亲、父亲和受影响的儿童三人组收集DNA)，利用来自科罗拉多大学和印第安纳大学早产儿的DNA，这些受试者是在科罗拉多大学和印第安纳大学进行的一项早产儿的前瞻性研究，这些早产儿是BPD的高危人群。

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.