端粒蛋白稳态异常和肺组织过早衰老的调控机制

Pulmonary senescence and fibrosis are underpinned by telomere dysfunction and premature senescence of alveolar stem cells. Environmental stress such as radiation and oxidative insult triggers telomere shortening in chronic lung disease and respiratory failure with unclear mechanisms. Our previous results showed that accelerated TPP1 turnover occurred in response to stress in the lung epithelial alveolar stem cells, resulting in telomere shortening, alveolar cellular senescence and lung fibrosis in mice. Overexpression of the deubiquitinase USP7 protected TPP1 from ubiquitin-dependent proteasome degradation, maintained telomere homeostasis, and reduced lung aging-related.phenotypes induced by stress. In this project, we will elucidate the protective mechanism of USP7 over TPP1 in mouse models and clinical samples. We will define the regulatory network of TPP1 proteostasis in the maintenance of telomere and alveolar stem cell homeostasis. By elucidating the protective mechanism of TPP1 and telomere maintenance in stress-induced lung aging and fibrosis, we will develop effective strategies and methods for the prophylactic and therapeutic potentials against premature pulmonary aging and fibrotic lesions.

应激如X射线引起端粒缩短，导致肺过早衰老甚至纤维化；但端粒缩短和肺组织过早衰老的机制尚未阐明。在前期工作中，我们发现应激引起端粒蛋白TPP1在肺泡干细胞中快速降解，导致端粒缩短、肺衰老和纤维化。通过筛选去泛素化酶，我们发现USP7阻止TPP1降解，保护端粒稳态，阻断因应激引起的肺衰老及纤维化。本项目将应用敲除小鼠模型及人肺组织样品，研究TPP1与USP7通过相互作用防止端粒损伤和肺衰老的机制；阐明在应激条件下USP7对TPP1和端粒保护的机制，及其在防止肺组织衰老、纤维化中的作用；阐明TPP1稳态与失稳态引起肺泡干细胞端粒损伤及异染色质形成障碍的分子网络，从而建立预防肺组织过早衰老的策略、方法和手段。

肺衰老相关性疾病在老年人群中发病率逐年升高，病情严重且无有效疗法。研究表明肺泡上皮细胞衰老，尤其是环境因子对肺衰老相关疾病的发生机制发挥重要的作用。本项目研究发现E3泛素连接酶FBW7和泛素蛋白酶USP7共同调节端粒及端粒蛋白TPP1的稳态，参与应激引起的肺泡干细胞衰老及相关疾病的发生；分子机制研究表明USP7通过调控端粒DNA损伤，端粒蛋白TPP1的稳态和端粒酶的招募调节肺泡干细胞衰老；探明了TPP1稳态调节蛋白FBW7和USP7在肺衰老相关疾病发生发展过程的分子调控机制；阐明了介导应激条件下维持端粒相关蛋白稳态及端粒DNA损伤在肺衰老相关疾病中的作用机制。我们的发现表明USP7抑制肺泡干细胞中端粒DNA损伤是防治肺泡干细胞衰老及肺纤维化分子机制中的关键一环，对增强肺泡干细胞抵抗环境应激引起损伤的能力以及探讨肺纤维化的防治策略，具有重要的科学意义。