HL-FAM13A Regulates the beta-catenin/Wnt Pathway in Chronic Obstructive Pulmonary Disease

HL-FAM13A 调节慢性阻塞性肺疾病中的 β-catenin/Wnt 通路

• 批准号: 9249096
• 负责人: Anny Xiaobo Zhou
• 金额: $ 44.38万
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249096
• 关键词: Acute; Air; Alleles; Alveolar; Antibodies; Attenuated; Biological; Biological Process; Candidate Disease Gene; Case-Control Studies; Cause of Death; Cell Differentiation process; Cell Proliferation; Cells; Chemicals; Chronic; Chronic Obstructive Airway Disease; Cigarette smoke-induced emphysema; Complex; Critical Pathways; Custom; Data; Development; Dissection; Elastases; Epithelial; Epithelial Cells; Exposure to; Family; Family suidae; Foundations; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Translation; Genetic study; Genotype; Hamman-Rich syndrome; Human; Immunoprecipitation; In Vitro; Injury; Knockout Mice; Knowledge; Label; Lung; Lung diseases; Mediating; Modeling; Molecular; Mus; Natural regeneration; Pancreatic Elastase; Pathogenesis; Pathway interactions; Phosphorylation; Predisposition; Protein phosphatase; Publishing; Pulmonary Emphysema; Pulmonary Surfactant-Associated Protein C; Regulation; Reporter; Research; Resistance; Respiratory physiology; Risk; Role; S-Phase Fraction; Sampling; Series; Smoker; Stem cells; Susceptibility Gene; Tamoxifen; Testing; Time; Translating; Variant; Work; base; beta catenin; cigarette smoking; gene function; genome wide association study; in vivo; inhibitor/antagonist; insight; lung development; lung injury; lung regeneration; lung repair; member; mouse model; novel; novel strategies; personalized medicine; public health relevance; repaired; risk variant

 DESCRIPTION (provided by applicant): HL-131. Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the U.S. It is also strongly influenced by cigarette smoking (CS) and genetic predisposition. A novel gene, FAM13A (family with sequence similarity 13, member A, with unknown function) has been consistently associated with susceptibility to COPD in case-control studies and with lung function in general population samples in genome-wide association studies (GWAS). Very recently, the COPD risk allele at the FAM13A locus was shown to be associated with increased expression of FAM13A in human lung samples. However, how this novel gene functions in vivo under CS-induced injury remains unknown. This substantial gap in our knowledge has greatly impeded translation of these genetic discoveries into a better understanding of COPD pathobiology and the huge potential of personalized medicine. Using a series of in vitro and in vivo approaches, we demonstrate that Fam13a-deficient mice (Fam13a-/-) showed attenuated emphysema induced by either CS or elastase. We also make the first connection between the novel GWAS gene FAM13A and the canonical Wnt pathway, essential for lung development as well as lung repair/regeneration in a variety of pulmonary diseases. In vitro, Fam13a facilitates assembly of protein phosphatase 2A(PP2A) with ß-catenin and promotes the phosphorylation and degradation of ß-catenin. Herein, we propose to extend our studies to a deep and comprehensive dissection of the regulation of the Wnt pathway by Fam13a and how their cross-talk mediates lung repair during CS-induced injury. In Aim 1, we will utilize a sensitive and specific GFP reporter mouse line for Wnt pathway activation to characterize the temporal and spatial regulation of Fam13a on the activity of the Wnt pathway during CS- exposure. In Aim 2, we will fully characterize how Fam13a modulates lung regeneration through inhibiting the Wnt pathway in the CS-induced injury model. In Aim 2.1,we will generate a double-deficient (Fam13a and ß- catenin) mouse line specifically in SP-C(surfactant protein C)-positive cells, facultative progenitor cells for lung reair after injury and then expose these mice to CS to determine whether activation of the Wnt pathway led to resistance to CS-induced airspace enlargement in Fam13a-/- mice. Roles of SP-C-positive cells in lung regeneration after CS-induced injury will be further explored in Aim 2.2. We will trace-label SPC-positive cells with GFP after tamoxifen induction in the presence or absence of Fam13a in vivo, then expose mice to acute and chronic CS to determine the role of the Fam13-Wnt axis in lung regeneration mediated by SPC-positive cells. In Aim 3, we will apply human primary alveolar and airway epithelial cells from COPD subjects with known genotypes at the FAM13A locus to determine whether differential cell proliferation and differentiation correlate with varying beta-catenin levels associated with FAM13A genotypes. Upon completion of this project, we will have a much deeper understanding of the role of Fam13a-ß-catenin/Wnt pathway during CS-induced injury and the mechanisms underlying human COPD.

 描述：HL-131。在全基因组关联研究中，对一般人群样本中的肺部功能（GWAS）在FAM13A基因座（GWAS）中对COPD的敏感性。我们所知的这一巨大差距很大程度上阻碍了这些遗传学发现，以更好地理解COPD病理生物学和一些个性化医学。 . WE ALSO Make The First Connection Between The Gwas Gene Fam13a and the Canonical Wnt Pathway Egeneration in a variety of pulmonary diseases. in Vitro, FAM13A Facilitates Assembly of Protein Phosphatase 2a (PP2a) With ß -catenin and Promotes The Phosphorylation and Catenin. Hrein ，我们建议将我们的研究扩展到FAM13A对Wnt途径的深度全面调节，以及在AIM 1的CS-Indury期间，Think如何介导肺修复，我们将利用和特定的GFP报告基因鼠标线来激活Wnt途径，以表征FAM13A在CS曝光期间的活动中的时间和spatilat离子。在SP-C（表面活性剂C） - 阳性细胞中，肺run和CS小鼠的辅助祖细胞确定CS诱导的FAM13A - / - 小鼠的激活途径是否激活了CS诱导的空域扩大威利·威尔特（Willy Wilther）在AIM 2.2中探索了我们将在tamoxifeon在E的存在或不存在FAM13A的情况下追踪标签SPC阳性细胞通过在FAM13A基因座的AIM 3 ROM COPD中，SPC阳性细胞确定差异细胞增殖和分化是否与FAM13A基因型的不同β-catenin水平相关。 CS串行伤害和人类COPD的机制。