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.

我们的研究重点是研究新生儿肺损伤机制。我们旨在确定小说 可以预防小儿肺部疾病的治疗靶标。支气管肺发育不良（BPD）是 早产婴儿的慢性肺部疾病。它主要是由用于维持的O2疗法引起的 早产婴儿。它是美国第二昂贵的儿科肺部疾病，也是BPD的事件 在呼吸疗法方面的最新进展仍然不变。 O2的机制 疗法引起BPD的理解很少。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针对机制的预防性部署 疗法。积累的证据表明，肺外基质（ECM）的异常形成 在O2诱导的期间，肺损伤在BPD的发展中具有主要作用。 O2引起的肺损伤 新生儿增加了蛋白氧化物（P-loxs）的表达。细胞分泌后并分解它们 成为成熟的Lox，具有在ECM蛋白中形成醛的能力。但是是否醛 在O2造成的新生儿肺中细胞外蛋白中的增加是未知的。以前我们发现了 TGFβ激活在小鼠幼犬BPD模型中具有直接作用。我们也确定 高氧化新生儿肺中的TGFβ激活增加了LOX的mRNA水平，ECM失调 形成。 LOX的表达增加似乎是由TGFβ触发的。这是因为TGFβ 增加其在培养的成纤维细胞中的mRNA表达和TGFβ神经化抑制了它们在 O2损伤的小鼠幼崽肺。然而，TGFβ提高LOX的表达的机制 成纤维细胞以及TGFβ刺激的LOX是否在O2造成的新生肺驱动器中的上调 醛的形成尚不清楚。该项目的中心假设是TGFβ诱导的表达 LOX会增加O2损伤的新生儿肺中的醛水平。在AIM 1中，我们建议确定第一个 TGFβ增加LOX在肺成纤维细胞中的表达以鉴定的细胞内途径 可能旨在减轻O2诱导的新生儿肺部疾病的信号传导元件。在AIM 2中，我们将测试 TGFβ和LOX如何增加高氧小鼠幼犬肺中的醛水平。在AIM 3中，我们将使用小说 醛节感应分子探针和MRI，以确定TGFβ中性化如何抑制体内醛 在O2诱导的小鼠幼崽中产生的肺损伤。成功完成该项目将确定新的 高氧化新生儿肺疾病的机制，可能是针对降低发展风险的 BPD在早产婴儿中。此外，它将提供对新生儿体内生物标志物的小说的概念概念 可以指导TGFβ靶向疗法的部署的肺部疾病。因为紧迫 疗法以防止BPD，这项工作的结果可能会刺激IN的快速发展和测试 O2受损害的新生儿肺中的体内醛含醛分子。