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Role of novel SphK1 inhibitor, PF543 in therapy of Bronchopulmonary dysplasia and Airway remodeling

新型SphK1抑制剂PF543在支气管肺发育不良和气道重塑治疗中的作用

基本信息

批准号：
10415183
负责人：
Anantha Harijith
金额：
$ 28.15万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415183
关键词：
Acute Address Adult Affect Alveolar Animal Model Brain Bronchopulmonary Dysplasia Caring Cells Childhood Chronic Clinical Clinical Trials Cognition Collagen Data Dependence Development Drug Kinetics Exposure to Functional disorder Gases Generations Growth Home Hyperoxia In Vitro Incidence Inflammation Inhalation Learning Disabilities Life Long-Term Effects Longevity Lung Magnetic Resonance Imaging Mediating Medical Modeling Morphology Mus Natural regeneration Neonatal Neonatal Hyperoxic Injury Newborn Infant Normalcy North America Oxygen Oxygen Therapy Care Pathogenesis Pathology Patients Pharmaceutical Preparations Physiological Plague Play Pregnancy Premature Birth Premature Infant Production Protein-Lysine 6-Oxidase Pulmonary Hypertension Reactive Oxygen Species Recovery Role Route SPHK1 enzyme Superoxide Dismutase Therapeutic Therapeutic Agents Treatment Efficacy Ventilator Wheezing airway hyperresponsiveness airway remodeling base cognitive function comparative crosslink effective therapy efficacy evaluation extracellular extreme prematurity free radical oxygen health disparity human old age (65+)infancy inhibitor intraperitoneal lung development lung volume mouse model neonatal mice novel novel therapeutics postnatal preterm newborn prevent pulmonary function repaired response small molecule inhibitor sphingosine 1-phosphate surfactant therapeutically effective translational potential underserved community

项目摘要

Bronchopulmonary Dysplasia (BPD), a debilitating condition affecting preterm newborns, is in part a consequence of ventilator care and inhaled oxygen (O2) therapy. Prolonged oxygen therapy is essential for survival of an extreme preterm born at 24 weeks gestation; however, it has deleterious consequences. Patients with severe BPD are often discharged home on oxygen therapy lasting many months. Alveolar simplification forms the morphological hallmark of BPD, while severe airway remodeling (AWRM) leads to intractable wheezing right from the neonatal stage. Sequelae such as wheezing, pulmonary hypertension and learning disabilities plague BPD patients in adult life. Despite advances in the understanding of pathophysiology of BPD, effective therapy remains elusive for this condition affecting more than 15,000 newborns per year in the US alone with a medical burden of $26.2 billion. In this context, we have identified a small molecule inhibitor, PF543, as a potential therapy for both BPD and AWRM. PF543 inhibits specifically sphingosine kinase (SphK) 1 that catalyzes formation of sphingosine-1-phosphate (S1P) from sphingosine, and S1P plays a critical role in the pathogenesis of BPD (10-12). Our recent preliminary results revealed that both BPD and AWRM were significantly ameliorated in neonatal Sphk1-/- mice (but NOT Sphk2-/-) exposed to hyperoxia (HO). Wild type (WT) newborn mice treated with PF543 during HO resulted in ameliorated BPD, AWRM and airway hyperreactivity (AHR) compared to controls. On a related note, we also observed that PF543 also inhibits S1P-mediated intracellular reactive oxygen species (ROS) generation. S1P/ROS also upregulate Lysyl oxidase (Lox). Lox promotes excess collagen cross-linking leading to BPD. Induction of Lox by HO was inhibited by PF543. Based on these exciting preliminary data, we hypothesized that “Inhibition of sphingosine kinase 1 by PF543 has a therapeutic role in the treatment of BPD and its sequela of AWRM & AHR”. BPD evolves through two critical stages of lung development following the saccular stage. The first stage is early alveolarization and AWRM during which the preterm neonate with developing BPD shows oxygen dependency. The second stage is late alveolarization and AWRM corresponding to recovery and repair during early infancy and childhood. We will validate our hypothesis by pursuing the following two specific aims that address the efficacy of PF543 in moderate and severe forms of BPD using our hyperoxia-neonatal mouse model that mimcs various pathology mile stones seen in clinical BPD. Specific Aim #1 will determine the therapeutic efficacy of PF543 in BPD during the early alveolar stage of lung development (acute hyperoxia model as in early stage BPD) and specific Aim #2: Determine the therapeutic efficacy of PF543 in BPD during late alveolar stage of lung development (chronic hyperoxia model as in advanced stage BPD). We will also determine the ability of PF543 to suppress the long term brain related cognition abonormalities seen in severe BPD. Once realized, the proposed body of work will dramatically increase the translational potential of PF543 as an effective therapeutic agent against BPD.

支气管肺发育不良 (BPD) 是一种影响早产新生儿的衰弱性疾病，部分原因是呼吸机护理和吸入氧气 (O2) 治疗的结果。长期吸氧治疗是对于妊娠 24 周出生的极端早产儿的生存至关重要；然而，它有有害的后果。患有严重 BPD 的患者通常需要吸氧才能出院治疗持续数月。肺泡简化形成 BPD 的形态学标志，而严重气道重塑（AWRM）会导致新生儿出现顽固性喘息阶段。喘息、肺动脉高压和学习障碍等后遗症困扰着 BPD 成年后的患者。尽管对 BPD 病理生理学的理解取得了进展，但有效的这种疾病每年影响超过 15,000 名新生儿，但治疗方法仍然难以捉摸。仅美国就有262亿美元的医疗负担。在此背景下，我们确定了一个小分子抑制剂 PF543，作为 BPD 和 AWRM 的潜在疗法。 PF543 抑制特别是鞘氨醇激酶 (SphK) 1，可催化 1-磷酸鞘氨醇的形成 (S1P) 来自鞘氨醇，S1P 在 BPD 的发病机制中发挥着关键作用 (10-12)。我们的最近的初步结果显示，BPD 和 AWRM 在新生 Sphk1-/- 小鼠（但不是 Sphk2-/-）暴露于高氧 (H2O)。野生型 (WT) 新生儿在 HO 期间接受 PF543 治疗的小鼠可改善 BPD、AWRM 和气道与对照组相比，过度反应（AHR）。在相关说明中，我们还观察到 PF543 也抑制 S1P 介导的细胞内活性氧 (ROS) 的产生。 S1P/ROS 也上调赖氨酰氧化酶 (Lox)。 Lox 会促进过量的胶原蛋白交联，从而导致 BPD。 PF543 抑制 H2O 对 Lox 的诱导。基于这些令人兴奋的初步数据，我们假设“PF543 对鞘氨醇激酶 1 的抑制具有治疗作用 BPD 的治疗及其 AWRM 和 AHR 后遗症”。BPD 的演变经历了两个关键时期囊状阶段之后的肺发育阶段。第一阶段是早期肺泡化以及 AWRM，在此期间患有 BPD 的早产儿表现出氧气依赖性。第二阶段是晚期肺泡化和AWRM，对应于期间的恢复和修复婴儿期早期和儿童期。我们将通过以下两个具体的研究来验证我们的假设旨在利用我们的技术解决 PF543 对中度和重度 BPD 的疗效高氧新生儿小鼠模型，模拟临床 BPD 中出现的各种病理里程碑。具体目标#1 将确定 PF543 在早期肺泡病期间 BPD 的治疗效果肺部发育阶段（BPD 早期的急性高氧模型）和具体目标#2：确定 PF543 对肺晚期肺泡期 BPD 的治疗效果发育（慢性高氧模型如晚期 BPD）。我们还将确定 PF543 抑制严重脑部长期相关认知异常的能力边缘性人格障碍。一旦实现，拟议的工作体系将极大地提高转化率 PF543 作为 BPD 有效治疗剂的潜力。