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.

我们的研究集中在新生儿肺损伤的机制的调查。我们的目标是确定新的 可以预防小儿肺部疾病的治疗靶点。支气管肺发育不良（BPD）是一种 早产儿的慢性肺病。它主要是由O2疗法引起的， 早产儿它是美国第二大最昂贵的儿科肺部疾病，BPD的发病率 尽管最近呼吸治疗取得了进展，但仍保持不变。O2的作用机制 引起BPD的治疗方法知之甚少。此外，没有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机制的部署， 治疗越来越多的证据表明，肺细胞外基质（ECM）的异常形成， 在O2-诱导的肺损伤过程中，BPD的发展起主要作用。氧致肺损伤 新生儿增加赖氨酰氧化酶原（p-LOX）的表达。在细胞分泌和分裂后， 成为成熟的LOX，其具有在ECM蛋白中形成醛的能力。但醛类是否 在O2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 TGFβ活化在小鼠幼仔BPD模型中BPD的发展中具有直接作用。我们还决定 高氧新生儿肺中TGFβ的激活增加了LOX的mRNA水平， 阵LOX表达的增加似乎直接由TGFβ触发。这是因为TGFβ 在培养的成纤维细胞中增加它们的mRNA表达，并且TGFβ中和抑制它们在成纤维细胞中的表达。 O2损伤小鼠幼仔肺。然而，TGFβ增加Lox表达的机制与TGF β抑制Lox表达的机制无关。 成纤维细胞和是否TGFβ刺激的LOX上调在O2损伤的新生儿肺驱动器 醛的形成是未知的。该项目的中心假设是，TGFβ诱导的 LOX增加了O2损伤的新生儿肺中的醛水平。在目标1中，我们建议首先确定 时间TGFβ增加肺成纤维细胞中LOX表达的细胞内途径，以鉴定 可能有针对性地减轻O2诱导的新生儿肺部疾病的信号传导元件。在目标2中，我们将测试 转化生长因子β和脂氧合酶如何增加高氧小鼠幼仔肺醛水平在目标3中，我们将使用一本小说 去敏感分子探针和MRI用于确定TGFβ-中和如何抑制体内醛 在O2诱导的小鼠幼仔肺损伤过程中产生。该项目的成功完成将确定新的 高氧新生儿肺疾病的机制，可能是有针对性的，以减少发展的风险 早产儿的BPD此外，它将提供一种新的新生儿体内生物标志物的概念验证 肺疾病，可以指导部署TGFβ靶向治疗。由于迫切需要 治疗诊断学来预防BPD，这项工作的结果可能会刺激快速发展和测试， 在O2损伤的新生儿肺中的体内去氧传感分子。