Dysregulated extracellular matrix metabolism: a basis for arrested alveolar development in bronchopulmonary dysplasia?

细胞外基质代谢失调：支气管肺发育不良肺泡发育停滞的基础？

• 批准号: 160966624
• 负责人: Professor Dr. Rory Edward Morty, Ph.D.
• 金额: --
• 依托单位: Abteilung Translationale Pneumologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/160966624?language=en
• 关键词: Dysregulated; extracellular; matrix; metabolism; basis

Bronchopulmonary dysplasia (BPD) is a key cause of morbidity and mortality in pediatric settings. The key feature of BPD is arrested late lung development, attributed to impaired septation (division of immature alveolar airspaces into mature alveoli). The basis of this impaired septation is not understood, but preliminary observations suggest that extracellular matrix (ECM) remodeling is impaired in affected lungs. This project proposal introduces a new idea in BPD pathogenesis, where it is hypothesized that over-stabilization of the ECM impedes normal ECM remodeling, and “locks” the lung structure, making the lung resistant to normal remodeling, which might underlie the arrested development of affected lungs. The proposed project has three primary goals: (i) to assess the ECM status and expression of ECM chaperones and stabilizing enzymes in the lung in clinical and experimental BPD; (ii) to identify ECM metabolism pathways relevant to late lung development, and (iii) to identify and validate which of those pathways are dysregulated in lungs affected with BPD. The long-term objectives of this project (which extend beyond the three-year project proposed here), aim to target both the enzyme systems that direct ECM maturation, and the underlying signaling pathways controlling them, to drive proper remodeling, or indeed, reverse-remodeling of affected, immature lungs. These approaches might promote and restore normal structure to lungs affected with BPD.

支气管肺发育不良（BPD）是儿科发病率和死亡率的主要原因。BPD的主要特征是肺发育晚期受阻，这归因于分隔受损（未成熟肺泡气腔分裂为成熟肺泡）。这种受损的分隔的基础尚不清楚，但初步观察表明，细胞外基质（ECM）重塑受损，在受影响的肺。该项目提案在BPD发病机制中引入了一个新的想法，其中假设ECM的过度稳定阻碍了正常的ECM重塑，并“锁定”肺结构，使肺抵抗正常重塑，这可能是受影响肺发育受阻的基础。拟议的项目有三个主要目标：（i）在临床和实验BPD中评估ECM状态和ECM分子伴侣和稳定酶在肺中的表达;（ii）鉴定与晚期肺发育相关的ECM代谢途径，以及（iii）鉴定和验证哪些途径在受BPD影响的肺中失调。该项目的长期目标（超出本文提出的三年期项目）旨在靶向指导ECM成熟的酶系统和控制它们的潜在信号通路，以驱动受影响的未成熟肺的适当重塑，或实际上是逆转重塑。这些方法可能会促进和恢复受BPD影响的肺的正常结构。