TGFB AND PULMONARY ALDEHYDES IN NEWBORN LUNG INJURY

TGFB 和肺醛在新生儿肺损伤中的作用

• 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
• 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

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.

我们的研究重点是探讨新生儿肺损伤的发生机制。我们的目标是识别小说 可预防儿童肺部疾病的治疗靶点。支气管肺发育不良(BPD)是一种 早产儿的慢性肺部疾病。这在很大程度上是由氧气疗法引起的，氧气疗法用于维持 早产儿。它是美国第二昂贵的儿科肺部疾病，也是BPD的发病率 保持不变，尽管最近在呼吸疗法方面取得了进展。氧气的作用机制 引起BPD的治疗方法知之甚少。此外，目前还没有有效的生物标志物或成像方法。 发现疾病的早期阶段或指导部署有针对性的机制预防 治疗。越来越多的证据表明，肺细胞外基质(ECM)的异常形成 O2诱导的肺损伤在BPD的发生发展中起主要作用。氧致大鼠肺损伤 新生儿增加了赖氨酰氧化酶原(p-LOXs)的表达。在细胞分泌和分裂后，它们 成为成熟的LOX，它们有能力在ECM蛋白质中形成醛。但是醛是不是 在氧气损伤的新生儿肺中细胞外蛋白的增加是未知的。之前我们发现 转化生长因子β的激活在BPD模型小鼠BPD的发生发展中起直接作用。我们还决定 转化生长因子β在高氧新生肺组织中的激活增加LOXs的表达并调节细胞外基质 队形。转化生长因子β可直接触发LOX的表达增加。这是因为转化生长因子β 转化生长因子β中和抑制其在成纤维细胞中的表达 O2-损伤的小鼠幼鼠肺。然而，转化生长因子β增加Loxs表达的机制 成纤维细胞与转化生长因子β是否促进氧损伤新生大鼠肺组织中LOX的上调 醛的形成是未知的。该项目的中心假设是转化生长因子β诱导的血管内皮生长因子 LOXS可增加氧气损伤新生儿肺中的乙醛水平。在目标1中，我们建议首先确定 检测转化生长因子β促进肺成纤维细胞LOX表达的细胞内途径 可能针对减轻O2诱导的新生儿肺部疾病的信号元件。在目标2中，我们将测试 转化生长因子β和脂氧合酶是如何增加高氧小鼠肺组织中醛含量的。在《目标3》中，我们将用一本小说 乙醛敏感分子探针和核磁共振确定转化生长因子β中和如何抑制体内乙醛 氧致小鼠肺损伤过程中的产生。该项目的成功完成将确定新的 高氧性新生儿肺病的机制可能是降低发病风险的靶点 早产儿的BPD。此外，它还将提供一种新的新生儿体内生物标记物的概念验证 可以指导转化生长因子β靶向治疗的部署的肺部疾病。因为迫切需要 为了预防BPD，这项工作的结果可能会刺激In的快速开发和测试 氧损伤的新生儿肺中的活体乙醛敏感分子。