Metabolic Control of Stemness in lung epithelial progenitors by FAM13A

慢性阻塞性肺疾病（COPD）是美国第三大死亡原因，缺乏 有效的药物治疗。最近的进展表明，有缺陷的肺修复/再生可能 会导致肺气肿在修复/再生过程中，组织祖细胞需要 最佳量的能量供应，以满足细胞增殖和分化的需求，这已经很好地 在其他器官的干细胞中，如肠干细胞、神经祖细胞和造血干细胞， 干细胞然而，在肺上皮祖细胞中干细胞的代谢控制仍然难以捉摸。 FAM 13 A（具有序列相似性13的家族，成员A）一直与以下疾病的易感性相关： 全基因组关联研究（GWAS）中的COPD。我们发表的工作表明，FAM 13 A是 主要表达于肺泡II型上皮细胞，被认为是肺干细胞。然而， Fam 13 a调节肺泡修复/再生，特别是通过调节肺上皮细胞的代谢 祖先仍然不完全了解。在上一个融资周期中，我们已经发布了Fam 13 a促进 β-连环蛋白的降解并抑制细胞生长。然而，β-连环蛋白的耗竭未能完全 在Fam 13-/-小鼠中观察到逆转表型，表明FAM 13 A调节的其他途径可能发挥作用 在肺修复/再生过程中。我们未发表的数据表明，Fam 13 a不仅对 Akt介导的生长因子信号传导，但也抑制能量主调节因子AMPK（c-AMP激活 在细胞系和原代鼠肺上皮细胞中， 肺上皮祖细胞中的Fam 13 a。因此，我们假设FAM 13 A可能作为一种关键的代谢酶， 通过耦合能量稳态与肺泡上皮细胞中细胞生长需求来转换细胞生长 在肺再生过程中。在本提案中，我们将通过综合方法来检验这一假设 包括体外生物化学测定、体内谱系追踪、烟雾诱导的肺气肿小鼠模型 基于CRISPR的基因组编辑和离体类器官共培养模型。成功完成该项目 将揭示FAM 13 A转导生长因子信号的分子机制， 通过相互作用其上游调节因子Akt和 下游效应物AMPK，从而可能提供新的抗COPD治疗剂。

Chronic obstructive pulmonary disease (COPD) ranks as the third leading cause of death in the U.S., lacking effective pharmacological treatment. Recent progress suggested that defective lung repair/regeneration likely contribute to emphysema development. During repair/regeneration process, tissue progenitor cells require optimal amount of energy supplies to fulfill cell proliferation and differentiation demands, which has been well documented in stem cells in other organs such as intestine stem cells, neuro-progenitors and hematopoietic stem cells. However, the metabolic control of stemness in lung epithelial progenitor cells remains elusive. FAM13A (family with sequence similarity 13, member A) has been consistently associated with susceptibility to COPD in genome-wide association studies (GWAS). Our published work has demonstrated that FAM13A is mainly expressed in alveolar type II epithelial cells, regarded as lung stem cells. However, whether and how Fam13a regulates alveolar repair/regeneration, especially through modulating metabolism in lung epithelial progenitors remain incompletely understood. In last funding cycle, we have published that Fam13a promotes the degradation of beta-catenin and inhibits cell growth. However, depletion of beta-catenin failed to completely revert phenotype seen in Fam13-/- mice, suggesting additional pathways regulated by FAM13A may play a role in the lung repair/regeneration process. Our unpublished data suggested that Fam13a not only responds to Akt-mediated growth factor signaling but also represses the energy master regulator AMPK (c-AMP activated kinase) in cell lines and primary murine lung epithelial cells, suggesting an undiscovered metabolic control by Fam13a in lung epithelial progenitors. We, therefore, hypothesize that FAM13A may act as a key metabolic switch for cell growth through coupling energy homeostasis with cell growth demands in alveolar epithelial cells during lung regeneration. In this proposal, we are going to test this hypothesis through integrative approaches including in vitro biochemical assays, in vivo lineage tracing, smoke-induced emphysema mouse models, CRISPR-based genome editing and ex vivo organoid co-culture models. Successful completion of this project will shed mechanistic insights into molecular mechanism by which FAM13A transduces growth factor signals to metabolic controls on stemness of lung epithelial progenitors through interacting its upstream regulator Akt and downstream effector AMPK thereby possibly offering novel anti-COPD therapeutics.