Investigation of the molecular mechanisms of premature lung aging and enhanced susceptibility for chronic lung diseases in a postnatal stress model

人口老龄化和相关疾病是欧洲和德国日益严重的公共卫生负担。老年人慢性肺病患病率的增加表明与年龄相关的肺内在防御和再生机制的丧失。DNA损伤和修复机制之间的平衡对于维持细胞完整性和过早衰老至关重要。在生命过程中由慢性氧化应激介导的DNA损伤的积累是衰老的主要决定因素，并且伴随着亚急性慢性炎症（炎症）、衰老和干细胞衰竭。生命中这些过程的早期激活可能会促进肺过早老化，并增加对慢性肺病的易感性。我们的临床和实验研究证实，发育过程中的不良影响与成年期肺功能受损有关。使用成熟的早期出生后应激模型，我们将炎症、DNA损伤、衰老和祖细胞丢失与长期结构变化相关联，从而获得COPD老年患者的肺特征。基于这些发现，我们现在的目标是研究在早期发育过程中对肺的急性损伤是否会诱导肺的过早老化，从而导致肺泡再生能力降低和对以后生活中慢性肺病的易感性增加。为了解决这一假设，我们追求以下目标：（1）在由氧化应激诱导的新生儿肺损伤的小鼠模型中破译整体和肺泡上皮细胞II型（ATII）特异性过早衰老过程和特征;（2）通过单细胞-RNASeq分析正常老化小鼠肺和暴露于氧化应激后的新生小鼠肺的细胞组成;（3）使用肺泡上皮细胞特异性Ercc 1基因敲除小鼠的创新模型研究肺发育晚期肺泡上皮细胞中DNA损伤累积作为肺过早衰老的触发因素;（4）鉴定衰老过程并确定新生儿肺损伤儿童肺中的二值化转录组衰老（BiTage）时钟。这个项目建议是衰老研究和肺生物学之间的合作方法。识别促进肺过早老化和增加慢性肺部疾病易感性的早期机制将为衰老相关的慢性肺部疾病提供预测标志物和新的治疗方法。

The aging population and associated diseases are a growing public health burden in Europe and Germany. The increase in prevalence of chronic lung diseases at older ages suggests an age-associated loss of lung-intrinsic defense and regenerative mechanisms. The balance between DNA damage and repair mechanisms is central for the maintenance of cell integrity and premature aging. Accumulation of DNA damage-mediated by chronic oxidative stress during life is a major determinant of aging and is accompanied by a subacute chronic inflammation (inflammaging), senescence, and stem cell exhaustion. Early activation of these processes in life could promote premature lung aging and increase susceptibility to chronic lung disease. Our clinical and experimental studies confirm that adverse influences during development are associated with impaired lung function in adulthood. Using a well-established early postnatal stress model, we have associated inflammation, DNA damage, senescence, and loss of progenitor cells with long-term structural changes, yielding characteristics of lungs from aging patients with COPD. Based on these findings, we now aim to investigate whether acute damage to the lung during early development induces premature aging of the lung resulting in reduced alveolar regenerative capacity and increased susceptibility to chronic lung disease later in life. To address this hypothesis, we pursue the following objectives: (1) To decipher global and alveolar epithelial cell type II (ATII)-specific premature aging processes and signatures in a murine model of neonatal lung injury induced by oxidative stress; (2) To analyze cell composition by single cell-RNASeq of normally aged mouse lungs and neonatal mouse lungs after exposure to oxidative stress; (3) Investigation of DNA damage accumulation in alveolar epithelial cells during late lung development as a trigger of premature lung aging using an innovative model of alveolar epithelial cell-specific Ercc1 knockout mice; (4) To identify aging processes and to determine binarized transcriptomic aging (BiTage) clock in lungs of children with neonatal lung injury. This project proposal is a collaborative approach between aging research and lung biology. Identification of early mechanisms that promote premature lung aging and increase the susceptibility to chronic lung disease will provide predictive markers and novel therapeutic approaches for aging-associated chronic lung diseases.