Metabolic mechanisms underlying bronchopulmonary dysplasia-associated pulmonary hypertension

支气管肺发育不良相关肺动脉高压的代谢机制

基本信息

批准号：
10736803
负责人：
Hongwei Yao
金额：
$ 65.74万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736803
关键词：
Acetyl Coenzyme A Acetylation Affect Alveolar Arterial Medias Attenuated Blood Vessels Bronchopulmonary Dysplasia Carnitine Carnitine Palmitoyltransferase I Cell Differentiation process Cells Characteristics Data Development Disease Disease Management Down-Regulation Endothelial Cells Endothelium Enzymes Exposure to Fetus Gene Expression Goals Hospitalization Human Hyperoxia In Vitro Infant Innovative Therapy Knockout Mice Levocarnitine Lung Mechanical ventilation Mediating Mesenchymal Metabolic Metabolism Mitochondria Molecular Mus Neonatal Hyperoxic Injury Newborn Infant Oxygen Pathogenicity Patients Play Predisposition Premature Infant Proliferating Protein Acetylation Pulmonary Hypertension Pulmonary Vascular Resistance Reporting Research Role Smooth Muscle Myocytes System Testing Up-Regulation Vasodilator Agents clinically relevant cost curative treatments defined contribution fatty acid metabolism fatty acid oxidation innovation lamb model long chain fatty acid mouse model nanoparticle nanoparticle delivery neonatal mice neonate new therapeutic target novel novel therapeutics oxidation pharmacologic premature lungs prevent primary pulmonary hypertension pulmonary vascular remodeling reduce symptoms response success therapeutic target transdifferentiation translational potential vascular smooth muscle cell migration vascular smooth muscle cell proliferation ventilation

项目摘要

SUMMARY Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants, caused by mechanical ventilation and hyperoxia amongst other factors. Thirty percent of infants with BPD develop pulmonary hypertension (PH), characterized by pulmonary vascular (PV) remodeling. There are no curative therapies for this disease. My long-term goal is to develop novel targeted therapies to treat BPD associated PH (BPD-PH). PV remodeling is characterized by increased pulmonary arterial media layer thickening. This results from proliferation of vascular smooth muscle cells (SMCs), or transdifferentiation from endothelial cells (ECs) to SMCs (i.e., endothelial-mesenchymal transition, EndoMT). We have shown that hyperoxia in newborn mice and mechanical ventilation in preterm lambs cause PV remodeling resulting in PH, which is associated with increased EndoMT. We preliminarily show that EndoMT is also observed in the lung of premature human infants requiring mechanical ventilation. Blocking EndoMT prevents the progression of neonatal hyperoxia-induced PV remodeling and PH in mice, suggesting that EndoMT plays a causative role in inducing PH. We observed no increase in EdU incorporation into SMCs in hyperoxia-exposed mice, suggesting proliferation in these cells does not contribute to PV remodeling in BPD-PH. We recently reported that neonatal hyperoxia causes a persistent reduction of endothelial carnitine palmitoyltransferase 1a (Cpt1a), the rate-limiting enzyme of the carnitine shuttle system responsible for transporting long-chain fatty acids into mitochondria for β-oxidation during fatty acid oxidation. Our preliminary data show that lung Cpt1a gene expression is also reduced in mechanically ventilated preterm lambs and premature human infants. Additionally, endothelial deletion of Cpt1a increases EndoMT and PV remodeling in neonatal mice after exposure to hyperoxia. Furthermore, pharmacological upregulation of Cpt1a attenuates EndoMT in vitro and prevents PV remodeling in neonatal mice in response to hyperoxia. Whether neonatal hyperoxia and mechanical ventilation reduce endothelial Cpt1a, leading to PH is yet to be determined. The central hypothesis is that neonatal hyperoxia and mechanical ventilation cause EndoMT by downregulating endothelial Cpt1a levels, thereby resulting in PV remodeling and PH. We will test this hypothesis in three Specific Aims. Aim 1 will determine the molecular mechanisms by which Cpt1a downregulation contributes to EndoMT. In Aim 2, we will define the contribution of endothelial Cpt1a reduction to BPD-PH and EndoMT. In Aim 3, we will evaluate endothelial Cpt1a as a therapeutic target for BPD-PH using both lamb and mouse models. The combination of clinically relevant lamb and mouse models with our newly generated EC-specific Cpt1a KO mice and the novel EC-targeted nanoparticle delivery system provides an innovative approach to uncover the mechanisms by which Cpt1a downregulation mediates EndoMT and its significant roles in BPD-PH. This contribution is significant because it is likely to result in new therapies specifically targeting endothelial Cpt1a or EndoMT in neonates to treat BPD-PH.

概括支气管肺发育不良（BPD）是早产儿的一种慢性肺部疾病，由机械性呼吸引起。 30% 的 BPD 婴儿会出现肺通气和高氧血症等因素。以肺血管（PV）重塑为特征的高血压（PH）尚无治疗方法。我的长期目标是开发新的靶向疗法来治疗 BPD 相关 PH (BPD-PH)。 PV 重塑的特点是肺动脉中层增厚。血管平滑肌细胞 (SMC) 的增殖，或从内皮细胞 (EC) 向 SMC 的转分化（即内皮间质转化，EndoMT）我们已经证明新生小鼠的高氧血症和早产羔羊的机械通气会导致 PV 重塑，从而导致 PH 升高，这与 PH 升高有关我们初步表明，在需要的早产儿的肺部也观察到了 EndoMT。阻断 EndoMT 可预防新生儿高氧诱导的 PV 进展。小鼠体内的重塑和 PH，表明 EndoMT 在诱导 PH 中起着致病作用。在高氧暴露的小鼠中，EdU 融入 SMC 的数量增加，表明这些细胞的增殖确实不会导致 BPD-PH 中的 PV 重塑。我们最近报道，新生儿高氧血症会导致持续性的。内皮肉碱棕榈酰转移酶 1a (Cpt1a)（肉碱限速酶）的减少穿梭系统负责将长链脂肪酸运输到线粒体中进行脂肪氧化过程中的β-氧化我们的初步数据表明，肺 Cpt1a 基因表达也因机械原因而降低。此外，通气的早产羔羊和早产人类婴儿中 Cpt1a 的内皮缺失也会增加。新生小鼠暴露于高氧后的 EndoMT 和 PV 重塑此外，药理学。 Cpt1a 的上调可在体外减弱 EndoMT 并防止新生小鼠响应于新生儿高氧和机械通气是否会降低内皮Cpt1a，导致PH？尚未确定的中心假设是新生儿高氧血症和机械通气导致。 EndoMT 通过下调内皮 Cpt1a 水平，从而导致 PV 重塑和 PH。三个具体目标 1 中的这一假设将确定 Cpt1a 的分子机制。下调有助于 EndoMT 在目标 2 中，我们将定义内皮 Cpt1a 减少的贡献。 BPD-PH 和 EndoMT 在目标 3 中，我们将使用内皮 Cpt1a 作为 BPD-PH 的治疗靶点进行评估。羔羊和小鼠模型将临床相关的羔羊和小鼠模型与我们最新的模型相结合。产生了 EC 特异性 Cpt1a KO 小鼠，新型 EC 靶向纳米颗粒递送系统提供了揭示 Cpt1a 下调介导 EndoMT 及其机制的创新方法在 BPD-PH 中发挥重要作用这一贡献意义重大，因为它可能会带来新的疗法。专门针对新生儿的内皮 Cpt1a 或 EndoMT 来治疗 BPD-PH。