Role of PDGF-A/PDFG-Receptor alpha signaling in normal and abnormal lung development

PDGF-A/PDFG-受体α信号传导在正常和异常肺发育中的作用

• 批准号: 185942956
• 负责人: Privatdozentin Dr. Anne Hilgendorff
• 金额: --
• 依托单位: Zentrum für Comprehensive Developmental Care (CDeC LMU)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/185942956?language=en
• 关键词: Role; PDGF; PDFG; Receptor; alpha

Mechanical ventilation with O2-rich gas (MV) is a life-saving remedy for respiratory failure but also promotes lung injury, which in neonates translates to defective alveolar septation, angiogenesis and elastin deposition resulting in lung growth arrest as seen in neonatal chronic lung disease (CLD). Adverse effects of MV on developing lungs have been ascribed to impaired signaling of various growth factors, including PDGF. A critical role of PDGF signaling in lung development emerged from the discovery that lungs of mice deficient in PDGF-A or its receptor (PDGF-Rα) showed impaired lung growth, leading to neonatal death or shortened survival. The failure in alveolar septation, leading to an emphysematous-like lung phenotype was attributed to lack of migration of alveolar smooth muscle progenitor cells (myofibroblasts, MFBs). Later studies showed that lambs with CLD had reduced lung expression of PDGF-A and PDGF-Rα. PDGF-A protein also was reduced in lungs of newborn mice with alveolar hypoplasia after 24h of MV. We recently found that 7d-old mice bearing a single allele of PDGF-Rα had larger and fewer alveoli and disordered lung elastin compared to WT controls. Lung pathology resembled CLD. Our goal now is to define the role of impaired PDGF signaling in the growth failure and impaired ECM remodeling seen in developing lungs exposed to MV. We will study how PDGF-Rα heterozygosity affects proliferation, migration and elastin synthesis of cultured lung MFBs, which express PDGF-Rα. We will see how PDGF-A treatment during cyclic stretch ± hyperoxia affects PDGF-Rα signaling in lung MFBs. In vivo studies will test how PDGF-Rα haploinsufficiency is involved in MV-induced lung growth arrest and aberrant elastin deposition in newborn mice and if PDGF-A treatment can prevent or attenuate adverse effects of MV. This work will yield new insights on how PDGF signaling regulates alveolar septation and matrix remodeling of the newborn lung, which will help formulate new strategies to promote lung growth during MV.

使用富氧气体（MV）的机械通气是呼吸衰竭的救生措施，但也会促进肺损伤，这在新生儿中转化为肺泡分隔缺陷、血管生成和弹性蛋白沉积，导致肺生长停滞，如新生儿慢性肺病（CLD）中所见。MV对发育中的肺的不良影响归因于各种生长因子（包括PDGF）的信号传导受损。PDGF信号传导在肺发育中的关键作用来自于发现PDGF-A或其受体（PDGF-Rα）缺陷的小鼠的肺显示肺生长受损，导致新生儿死亡或生存期缩短。导致肺气肿样肺表型的肺泡分隔失败归因于肺泡平滑肌祖细胞（肌成纤维细胞，MFB）缺乏迁移。后来的研究表明，CLD羔羊肺组织中PDGF-A和PDGF-Rα的表达减少。肺泡发育不全的新生小鼠在MV 24小时后肺中的PDGF-A蛋白也减少。我们最近发现，与WT对照组相比，携带PDGF-Rα单等位基因的7日龄小鼠的肺泡更大、更少，肺弹性蛋白紊乱。肺部病理学类似CLD。我们现在的目标是确定受损的PDGF信号传导在暴露于MV的发育中的肺中观察到的生长衰竭和受损的ECM重塑中的作用。我们将研究PDGF-Rα杂合性如何影响表达PDGF-Rα的培养肺MFB的增殖、迁移和弹性蛋白合成。我们将观察PDGF-A在循环牵张±高氧期间如何影响肺MFB中的PDGF-Rα信号传导。体内研究将测试PDGF-Rα单倍不足如何参与新生小鼠MV诱导的肺生长停滞和异常弹性蛋白沉积，以及PDGF-A治疗是否可以预防或减轻MV的不良反应。这项工作将产生新的见解PDGF信号如何调节肺泡分隔和基质重塑的新生儿肺，这将有助于制定新的策略，以促进肺生长在MV。