TGFB AND PULMONARY ALDEHYDES IN NEWBORN LUNG INJURY

TGFB 和肺醛在新生儿肺损伤中的作用

基本信息

批准号：
10009822
负责人：
JESSE D ROBERTS
金额：
$ 42.54万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10009822
关键词：
Air Aldehydes Alveolar Amino Acids Antibodies Biological Markers Breathing Bronchopulmonary Dysplasia Caring Cell Line Cell secretion Cessation of life Childhood Chronic lung disease Collagen Consumption Development Disease Elastin Elements Enzymes Excision Extracellular Matrix Extracellular Matrix Proteins Extracellular Protein Family member Fibrillar Collagen Fibroblasts Generations Growth and Development function Hospitalization Hydroxylysine Imaging Device Immunoblotting Immunohistochemistry Incidence Infant Investigation LOX gene Life Lung Lung diseases Lysine Magnetic Resonance Imaging Maps Measurement Mediating Medical Messenger RNA Methods Modeling Molecular Marker Activity Molecular Probes Mus N-terminal Newborn Infant Oxygen Pathogenesis Pathologic Pathway interactions Play Premature Infant Preventive therapy Protein-Lysine 6-Oxidase Pulmonary Valve Insufficiency Recurrence Research Respiratory Therapy Risk Role Saccule structure Signal Transduction TGFB1 gene Testing Time Transforming Growth Factor beta Transgenic Mice Tropoelastin United States Up-Regulation Work cost crosslink extracellular functional group imaging modality in vivo injured kinase inhibitor knock-down lung development lung injury mRNA Expression new therapeutic target novel premature lungs preterm newborn prevent promoter pup small molecule targeted treatment theranostics therapeutic target

项目摘要

Our research focuses on the investigation of mechanisms of newborn lung injury. We aim to identify novel therapeutic targets that can prevent pediatric pulmonary disease. Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurely born infants. It is largely caused by O2 therapies that are used to sustain premature babies. It is the second most costly pediatric lung disease in the U.S. and the incidence of BPD remains unchanged despite recent advancements in respiratory therapies. The mechanisms by which O2 therapies cause BPD are poorly understood. Moreover, there are no effective biomarkers or imaging methods that detect the early stages of the disease or guide the deployment of mechanism-targeted preventive therapies. Accumulating evidence suggests that abnormal formation of the lung extracellular matrix (ECM) during O2-induced lung injury has a primary role in the development of BPD. O2-induced lung injury in newborns increases the expression of pro-lysyl oxidases (p-LOXs). After cellular secretion and cleavage they become mature LOXs, which have the capability to form aldehydes in ECM proteins. But whether aldehydes are increased in extracellular proteins in the O2-injured newborn lung is unknown. Previously we discovered that TGFβ activation has a direct role in BPD development in mouse pup BPD models. We determined also that TGFβ activation in hyperoxic newborn lungs increases the mRNA levels of LOXs and dysregulates ECM formation. The increased expression of LOXs appears directly triggered by TGFβ. This is because TGFβ increases their mRNA expression in cultured fibroblasts and TGFβ neutralization inhibits their expression in O2-injured mouse pup lungs. However, the mechanisms by which TGFβ increases the expression of LOXs in fibroblasts and whether the TGFβ-stimulated up-regulation of LOXs in the O2-injured newborn lung drives aldehyde formation are unknown. The central hypothesis of this project is that TGFβ-induced expression of LOXs increases aldehyde levels in the O2-injured newborn lung. In Aim 1, we propose to identify for the first time the intracellular pathways by which TGFβ increases the expression of LOXs in lung fibroblasts, to identify signaling elements that might be targeted to mitigate O2-induced newborn lung disease. In Aim 2, we will test how TGFβ and LOXs increase aldehyde levels in hyperoxic mouse pup lung. In Aim 3, we will use a novel aldehyde-sensing molecular probe and MRI to determine how TGFβ-neutralization inhibits in vivo aldehyde generation during O2-induced lung injury in mouse pups. Successful completion of this project will identify new mechanisms for hyperoxic newborn lung disease that might be targeted to decrease the risk of developing BPD in preterm babies. Moreover, it will provide a proof-in-concept of a novel in vivo biomarker of newborn lung disease that could guide the deployment of TGFβ-targeting therapies. Because of the pressing need for theranostics to prevent BPD, the results of this work will likely stimulate rapid development and testing of in vivo aldehyde-sensing molecules in the O2-injured newborn lung.

我们的研究重点是新生儿肺损伤机制的研究，旨在找出新的机制。支气管肺发育不良（BPD）是一种早产儿的慢性肺部疾病主要是由用于维持生命的氧气疗法引起的。它是美国第二大昂贵的儿科肺部疾病，也是 BPD 的发病率。尽管呼吸疗法最近取得了进展，但 O2 的作用机制仍然没有改变。此外，尚无有效的生物标志物或成像方法。检测疾病的早期阶段或指导部署有针对性的预防措施越来越多的证据表明肺细胞外基质（ECM）的异常形成。 O2 引起的肺损伤在 BPD 的发生中起主要作用。新生儿在细胞分泌和裂解后会增加赖氨酰氧化酶原 (p-LOX) 的表达。成为成熟的LOX，具有在ECM蛋白中形成醛的能力，但是否是醛。此前我们发现，氧气损伤的新生儿肺中细胞外蛋白是否增加尚不清楚。我们还确定，TGFβ 激活在小鼠 BPD 模型中的 BPD 发展中具有直接作用。高氧新生儿肺中 TGFβ 的激活会增加 LOX 的 mRNA 水平并失调 ECM LOX 表达的增加似乎是由 TGFβ 直接触发的。增加其在培养的成纤维细胞中的 mRNA 表达，而 TGFβ 中和则抑制其在培养的成纤维细胞中的表达然而，O2 损伤的小鼠幼仔肺中 TGFβ 增加 LOX 表达的机制。成纤维细胞以及 TGFβ 刺激的 LOX 上调是否会驱动 O2 损伤的新生儿肺该项目的中心假设是 TGFβ 诱导的表达。 LOX 会增加受 O2 损伤的新生儿肺中的醛水平。在目标 1 中，我们建议首先进行鉴定。对 TGFβ 增加肺成纤维细胞中 LOX 表达的细胞内途径进行计时，以确定在目标 2 中，我们将测试可能用于减轻 O2 引起的新生儿肺部疾病的信号元件。 TGFβ 和 LOX 如何增加高氧小鼠幼崽肺中的乙醛水平在目标 3 中，我们将使用一种新颖的方法。醛传感分子探针和 MRI 以确定 TGFβ 中和如何抑制体内醛该项目的成功完成将鉴定新的小鼠幼崽中氧气诱导的肺损伤过程中的一代。高氧新生儿肺病的机制可能旨在降低发生风险此外，它还将为早产儿的 BPD 提供新的新生儿体内生物标志物的概念验证。肺部疾病可以指导 TGFβ 靶向疗法的部署。治疗诊断学来预防 BPD，这项工作的结果可能会刺激快速开发和测试氧气损伤的新生肺中的体内醛敏感分子。