Metabolic Control of Stemness in lung epithelial progenitors by FAM13A

FAM13A 对肺上皮祖细胞干性的代谢控制

• 批准号: 10321285
• 负责人: Anny Xiaobo Zhou
• 金额: $ 66.74万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321285
• 关键词: 5' -AMP-activated protein kinase; Address; Alveolar; Binding; Biochemical; Biological; Biological Assay; Cause of Death; Cell Differentiation process; Cell Line; Cell Proliferation; Cells; Chronic Obstructive Pulmonary Disease; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Coupled; Couples; Coupling; Cues; Cyclic AMP-Dependent Protein Kinases; Data; Development; Energy Supply; Epithelial; Epithelial Cells; Exposure to; Family; Fatty Acids; Funding; Genes; Genetic; Genetic Determinism; Glycolysis; Goals; Growth; Growth Factor; Hematopoietic stem cells; Homeostasis; Human; In Vitro; Intestines; Knock-in Mouse; Knock-out; Label; Lipids; Lung; Lung Capacity; Mediating; Metabolic; Metabolic Control; Metabolism; Mitochondria; Modeling; Molecular; Mus; Natural regeneration; Organ; Organoids; Pathway interactions; Patients; Pharmacological Treatment; Phenotype; Phosphorylation; Play; Predisposition; Process; Production; Protein Kinase; Protein Kinase C; Proteins; Public Health; Publishing; Pulmonary Emphysema; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Smoke; Spirometry; Tamoxifen; Testing; Therapeutic; Tissues; Ubiquitination; WNT Signaling Pathway; Work; airway obstruction; alveolar epithelium; base; beta catenin; cell growth; cigarette smoking; design; epithelial stem cell; extracellular; genome editing; genome wide association study; improved; in vivo; inhibitor; injury and repair; insight; lipid metabolism; lung injury; lung regeneration; lung repair; meetings; member; mouse model; multicatalytic endopeptidase complex; novel; overexpression; progenitor; repaired; risk variant; sensor; smoking exposure; stem cells; stemness; treatment strategy; ubiquitin-protein ligase

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.

慢性阻塞性肺疾病（COPD）是美国第三大死亡原因，缺乏 有效的药理治疗。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源供应，这已经很好 记录在其他器官中的干细胞中，例如肠道干细胞，神经 - 促进剂和造血 干细胞。然而，肺上皮祖细胞中干性的代谢控制仍然难以捉摸。 FAM13A（具有序列相似性的家庭13，成员a）一直与易感性相关 全基因组关联研究（GWAS）中的COPD。我们发表的工作表明Fam13a是 主要在肺泡II型上皮细胞中表达，被视为肺干细胞。但是，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 祖细胞仍然不完全理解。在上一个融资周期中，我们发表了Fam13a促进的 β-catenin的降解并抑制细胞生长。但是，β-catenin的耗竭未能完全 恢复FAM13 - / - 小鼠中看到的表型，建议由FAM13A调节的其他途径可能起作用 在肺修复/再生过程中。我们未发表的数据表明，FAM13A不仅回应 Akt介导的生长因子信号传导，但也抑制能量主调节器AMPK（C-AMP激活 激酶）在细胞系和原发性鼠肺上皮细胞中，表明未发现的代谢对照 FAM13A在肺上皮祖细胞中。因此，我们假设FAM13A可能充当关键代谢 切换细胞生长，通过偶联能量稳态与肺泡上皮细胞的细胞生长需求转换 在肺部再生期间。在此提案中，我们将通过综合方法检验这一假设 包括体外生化测定，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器官共培养模型。成功完成该项目 FAM13A将生长因子信号传递到分子机制的机理将提供机械洞察力 通过相互作用的上游调节剂AKT和 下游效应子AMPK因此可能提供新颖的抗COPD疗法。