Novel therapeutic targets for bronchopulmonary dysplasia-associated pulmonary hypertension

项目总结/摘要 肺动脉高压（PH）是一种复杂的多因素疾病，具有多种表现， 相关诊断和潜在原因。世界卫生组织将PH分为5个临床组， 这些分类经常被修改，最近一次是在2013年，这证明了该疾病的复杂性。 作为一名早产学家，我对早产的并发症非常感兴趣， 并发症是支气管肺发育不良（BPD），这是一种慢性肺部疾病，影响这些前者 早产儿一直到成年。WHO分类系统将BPD相关PH置于第3组或PH 与呼吸系统疾病有关。PH的发病机制可能涉及许多不同的细胞机制， 但大多数形式的PH，包括BPD相关的PH，涉及会聚的生化途径。该途径 我之所以对它感兴趣，是因为它在血管收缩和血管收缩中起着关键作用， 重构（PH的标志）是L-精氨酸/NO途径。精氨酸可被一氧化氮代谢 合成酶（NOS），使有效的血管扩张剂NO，或由脱氢酶，多胺和脯氨酸的第一步 合成，对于血管重塑期间发生的细胞增殖至关重要。不对称 二甲基精氨酸（dimethylarginine，ADMA）是一种内源性NOS抑制剂，能被NG降解，NG-二甲基精氨酸 二甲基氨基水解酶（DDAH），允许增强内皮细胞中的内源性NO产生。 L-精氨酸/NO通路中的单核苷酸多态性（SNP）与全身性 高血压和肺部疾病，然而，它们在PH中的作用，特别是BPD相关的PH，还没有被 研究了我们的初步临床数据表明，第一次，有生物标志物参与了L- 精氨酸/NO途径，可能在早产儿中差异表达，继续发展BPD- 与未发生PH的BPD患者相比，我们最近有3篇文献 证明差异表达;在腺苷酸酶1（ARG 1）基因，血浆ADMA水平和SNP的SNP DDAH 1基因。我们的目标是利用这些新颖的、令人兴奋的和重要的初步临床发现， 完成一系列研究，以提供有针对性的研究培训，表征细胞机制 ARG 1和DDAH 1在体外的潜在作用，以及确定潜在的治疗 在BPD相关PH的动物模型中预防或治疗BPD相关PH的策略。我们将 通过围绕我们的转化研究战略的结构化培训计划实现这一目标 其具有3个具体目的：1）测试抑制ARG 1功能将增加NO产生的假设， 肺内皮细胞; 2）测试抑制DDAH 1功能将减少NO的假设 3）检验ARG 1的条件性小鼠敲除 将减弱PH，而DDAH 1的条件性小鼠敲除将加剧PH。 我们的目标是探索ARG 1和/或DDAH 1作为创新治疗药物的潜力。 BPD相关PH的靶点。

PROJECT SUMMARY/ABSTRACT Pulmonary hypertension (PH) is a complex multifactorial disease with a multitude of presentations, associated diagnoses, and underlying causes. The WHO has classified PH into 5 clinical groups, and as a testament to the complexity of the disease these classifications are frequently modified, most recently in 2013. As a neonatologist, I am very interested in the complications of preterm birth and the most common complication is bronchopulmonary dysplasia (BPD), which is a chronic lung disease that affects these former preterm infants well into adulthood. The WHO classification system puts BPD-associated PH in group 3 or PH associated with respiratory disease. The pathogenesis of PH can involve many different cellular mechanisms, but most forms of PH, including BPD-associated PH, involve converging biochemical pathways. The pathway that I have become interested in due to its pivotal involvement in both vasoconstriction and vascular remodeling (the hallmarks of PH) is the L-arginine/NO pathway. L-arginine can be metabolized by nitric oxide synthase (NOS) to make the potent vasodilator NO, or by arginase, the first step in polyamine and proline synthesis, vital for the cellular proliferation that occurs during vascular remodeling. Asymmetric dimethylarginine (ADMA), an endogenous NOS inhibitor, can be degraded by NG, NG-dimethylarginine dimethylaminohydrolase (DDAH), allowing for enhanced endogenous NO production in endothelial cells. Single nucleotide polymorphisms (SNPs) in the L-arginine/NO pathway have been associated with systemic hypertension and lung diseases, however their role in PH and specifically, BPD-associated PH, have not been studied. Our preliminary clinical data indicates, for the first time, that there are biomarkers involved in the L- arginine/NO pathway that may be differentially expressed in preterm infants that go on to develop BPD- associated PH compared to patients with BPD who do not develop PH. Indeed, we have 3 recent publications demonstrating differential expression; a SNP in the arginase 1 (ARG1) gene, plasma ADMA levels, and a SNP in the DDAH1 gene. Our goal is to take these novel, exciting, and important preliminary clinical findings and complete a series of studies in order to provide targeted research training, characterizing cellular mechanisms underlying the potential effects of ARG1 and DDAH1 in vitro, as well as identifying potential therapeutic strategies to either prevent or treat BPD-associated PH in an animal model of BPD-associated PH. We will achieve this goal through a structured training program that revolves around our translational research strategy which has 3 specific aims: 1) to test the hypothesis that inhibiting ARG1 function will increase NO production in pulmonary endothelial cells; 2) to test the hypothesis that inhibiting DDAH1 function will decrease NO production in pulmonary endothelial cells; 3) to test the hypothesis that a conditional mouse knock-out of ARG1 will attenuate PH, while a conditional mouse knock-out of DDAH1, will exacerbate PH, in a mouse model of BPD-associated PH. Our goal is to explore the potential for ARG1 and/or DDAH1 as innovative therapeutic targets for BPD-associated PH.