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）是由机械引起的早产婴儿的慢性肺疾病通风和高氧还包括其他因素。 BPD的婴儿中有30％发育肺部高血压（pH），其特征是肺血管（PV）重塑。没有治疗疗法这种疾病。我的长期目标是开发新型的靶向疗法来治疗BPD相关的pH（BPD-PH）。 PV重塑的特征是肺动脉培养基层增厚增加。这是由血管平滑肌细胞（SMC）的增殖，或从内皮细胞（EC）转变为SMC （即，内皮 - 间质转变，胚胎）。我们已经证明了新生小鼠的高氧早产羔羊的机械通气会导致PV重塑，导致pH，这与增加有关 endomt。我们初步表明，在需要的早产婴儿的肺中也观察到内托机械通气。阻塞胚胎阻止新生儿高氧诱导的PV的进展小鼠的重塑和pH值，表明内粒在诱导的pH中起致病作用。我们观察到没有在暴露高氧小鼠中掺入SMC中的EDU的增加，表明这些细胞中的增殖IN 在BPD-PH中不促进PV重塑。我们最近报道，新生儿高氧会导致持久性降低内皮肉碱棕榈酰转移酶1A（CPT1A），肉碱的速率限制酶班车系统负责将长链脂肪酸运输到线粒体中，以在脂肪中进行β-氧化酸性氧化。我们的初步数据表明，肺CPT1A基因表达也降低了通风的早产羔羊和早产婴儿。另外，CPT1A的内皮缺失增加暴露于高氧后，新生儿小鼠的胚胎和PV重塑。此外，药理学 CPT1A的上调减弱了体外胎盘的体外，并防止新生儿小鼠的PV重塑。高氧。新生儿高氧和机械通气是否减少了内皮CPT1a，导致pH是尚待确定。中心假设是新生儿高氧和机械通气导致通过下调内皮CPT1A水平的胚胎，从而导致PV重塑和pH。我们将测试这是三个特定目标的假设。 AIM 1将确定CPT1A的分子机制下调有助于胚胎。在AIM 2中，我们将定义内皮CPT1A减少的贡献到bpd-ph和endomt。在AIM 3中，我们将评估内皮CPT1A作为BPD-PH的治疗靶标羔羊和鼠标模型。临床上相关的羔羊和鼠标模型与我们的新的结合生成的EC特异性CPT1A KO小鼠和新型的EC靶向纳米颗粒输送系统提供了一个创新的方法是揭示CPT1A下调介导endomt及其的机制在BPD-PH中的重要作用。这种贡献很重要，因为它可能会导致新的疗法特别针对新生儿中的内皮CPT1A或内胞菌治疗BPD-PH。