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 有助于肺气肿的发展。在修复/再生过程中，组织祖细胞需要 满足细胞增殖和分化需求的最佳能量供应量，这已得到很好的证实 记录在其他器官的干细胞中，例如肠干细胞、神经祖细胞和造血细胞 干细胞。然而，肺上皮祖细胞干性的代谢控制仍然难以捉摸。 FAM13A（序列相似性为 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）中的慢性阻塞性肺病。我们发表的工作表明 FAM13A 是 主要表达于肺泡II型上皮细胞，被视为肺干细胞。然而，是否以及如何 Fam13a 调节肺泡修复/再生，特别是通过调节肺上皮的代谢 祖先仍然不完全了解。在上一个融资周期中，我们发布了 Fam13a 促进 β-连环蛋白的降解并抑制细胞生长。然而，β-连环蛋白的消耗未能完全 恢复 Fam13-/- 小鼠中观察到的表型，表明 FAM13A 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 Fam13a 不仅响应 Akt 介导的生长因子信号转导同时也抑制能量主调节器 AMPK（c-AMP 激活 激酶）存在于细胞系和原代小鼠肺上皮细胞中，表明通过 肺上皮祖细胞中的 Fam13a。因此，我们假设 FAM13A 可能作为一个关键的代谢 通过将能量稳态与肺泡上皮细胞中的细胞生长需求耦合来切换细胞生长 在肺再生期间。在这个提案中，我们将通过综合方法来检验这个假设 包括体外生化测定、体内谱系追踪、烟雾诱发的肺气肿小鼠模型、 基于 CRISPR 的基因组编辑和离体类器官共培养模型。本项目顺利完成 将深入了解 FAM13A 将生长因子信号转导为 通过上游调节剂 Akt 和肺上皮祖细胞干性的相互作用进行代谢控制 下游效应器 AMPK 从而可能提供新型的抗 COPD 疗法。

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 Our unpublished data suggested that Fam13a not only responds to Akt-mediated growth factor signaling but also represses the energy master regulator AMPK (c-AMP activated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.