Hox5 gene regulation of lung fibroblasts and distal lung extracellular matrix

Hox5基因对肺成纤维细胞和远端肺细胞外基质的调控

• 批准号: 10202716
• 负责人: Deneen M Wellik
• 金额: $ 44.28万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202716
• 关键词: Adhesions; Adult; Alleles; Alveolar; Animals; Area; Automobile Driving; Basement membrane; Behavior; Biology; Birth; Breathing; Bronchopulmonary Dysplasia; Cell Adhesion; ChIP-seq; Collagen; Complex; Data; Defect; Development; Disease; Distal; Doxycycline; Elasticity; Elastin; Embryo; Event; Exhibits; Extracellular Matrix; Family; Fibroblasts; Fibronectins; Gases; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Growth; Homeostasis; Human; ITGA5 gene; Impairment; In Vitro; Integrins; Knock-in; Knowledge; Lead; Life; LoxP-flanked allele; Lung; Lung Compliance; Maintenance; Mechanics; Mediating; Mesenchymal; Mesenchyme; Mesoderm; Molecular; Morphology; Mus; Mutant Strains Mice; Myofibroblast; Pathway interactions; Patients; Phase; Phenotype; Process; Publishing; Pulmonary Emphysema; Pulmonary function tests; Regulation; Role; Stretching; Structure; Structure of parenchyma of lung; Surface; Testing; Therapeutic; Tissues; Work; base; cell type; gene function; idiopathic pulmonary fibrosis; in vivo; interstitial; lung development; lung volume; mouse model; mutant; neonatal death; paralogous gene; postnatal; postnatal development; prevent; pulmonary function; transcription factor; transcriptome sequencing

ABSTRACT Alveologenesis occurs during postnatal development in humans and mice and this process allows for the growth of gas exchange surface area of the lung. One of the key events during this phase is the establishment of the elastin-based matrix in the distal airway. The incorporation of elastin into the existing lung matrix provide the elasticity that allows the distal airways to stretch and recoil effectively during breathing and mesodermally-derived SMA+ lung fibroblasts are key drivers of this process. Our previously published work has shown that the Hox5 genes are exclusively expressed in the mesenchyme of the lung and that loss of all three Hox5 genes leads to early, severe developmental lung defects and neonatal death. Four-allele, compound Hox5 mutant mice (Hox5 AabbCc) are born in Mendelian ratios and are phenotypically normal at birth, however, they develop alveolar simplification at postnatal stages. Consistent with a direct role for Hox5 genes in alveologenesis, the expression levels of all three Hox5 genes are highest during early postnatal stages when the bulk of alveologenesis occurs, higher than observed at any embryonic stage and these genes remain expressed through adult life. Using a newly generated conditional allele for Hoxa5, we show that conditional deletion of Hoxa5 in the lung mesenchyme beginning at birth results in an alveolar simplification phenotype postnatally. Hox5 mutant animals exhibit abnormal myofibroblast morphology and impaired function. Hox5 mutant fibroblasts demonstrate defects in cell adhesion and the expression of Integrin 5 and 1 are down- regulated. The continuing importance of Hox5 function at all stages is highlighted by surprising preliminary evidence that deletion of Hoxa5 at later stages (after the establishment of the elastin-based matrix) leads to rapid loss of the integrity of the elastin matrix. In this proposal, we will interrogate the cellular and molecular mechanisms of Hox5 regulation of lung mesenchyme during alveolar development, remodeling and homeostasis.

抽象的 肺单术发生在人类和小鼠产后发育期间，此过程允许 为了生长肺的气体交换表面积。在此阶段的关键事件之一是 在远端气道中建立基于弹性蛋白的矩阵。将弹性蛋白掺入 现有的肺部基质提供了弹性，使远端气道有效伸展和后退 在呼吸和中层衍生的SMA+肺成纤维细胞中，这是此过程的关键驱动力。我们的 以前发表的工作表明，HOX5基因仅在 肺间充质和所有三个HOX5基因的丧失导致早期，严重的发育 肺部缺陷和新生儿死亡。四等位基因，复合HOX5突变小鼠（HOX5 AABBCC）出生于 孟德尔的比例，在出生时表型正常，但是，它们在 产后阶段。与HOX5基因在肺单术中的直接作用一致，表达水平 在大部分肺单术时，所有三个HOX5基因中的所有三个HOX5基因均为最高 发生，比在任何胚胎阶段观察到的高，这些基因仍然通过成人表达 生活。使用新生成的有条件等位基因作为Hoxa5，我们显示了Hoxa5的条件删除 在出生时开始的肺间质中，产后会导致Allool简化表型。 HOX5突变动物暴露了异常的肌纤维细胞形态和功能受损。 HOX5突变体 成纤维细胞表现出细胞粘附缺陷，整联蛋白5和1的表达是下降的 受监管。 Hox5功能在各个阶段的持续重要性都令人惊讶地突出显示 初步证据表明，在以后的阶段删除Hoxa5（建立基于弹性蛋白的 矩阵）导致弹性蛋白基质的完整性迅速丧失。在此提案中，我们将审问 肺泡期间肺间隙的HOX5调节的细胞和分子机制 开发，改建和体内平衡。

项目成果

The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function.

• DOI: 10.3389/fcell.2021.767454
• 发表时间: 2021
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Li MH;Marty-Santos LM;van Ginkel PR;McDermott AE;Rasky AJ;Lukacs NW;Wellik DM
• 通讯作者: Wellik DM