Hox5 gene regulation of lung fibroblasts and distal lung extracellular matrix

摘要 肺泡发生发生在人类和小鼠的出生后发育过程中， 肺的气体交换表面积的增长。这一阶段的关键事件之一是 在远端气道中建立弹性蛋白基质。将弹性蛋白结合到 现有的肺基质提供了弹性 在呼吸过程中，中胚层来源的SMA+肺成纤维细胞是该过程的关键驱动因素。我们 先前发表的工作表明，Hox5基因只在 肺间充质和所有三个Hox5基因的丢失导致早期，严重的发育障碍， 肺缺陷和新生儿死亡。四等位基因复合Hox 5突变小鼠（Hox 5 AabbCc）出生于 孟德尔比率和表型在出生时正常，然而，他们在出生时会出现肺泡简化 产后阶段。与Hox 5基因在肺泡发生中的直接作用一致， 所有三个Hox5基因的表达在出生后早期阶段最高， 发生，高于在任何胚胎阶段观察到的，这些基因仍然表达，通过成人 生活使用新产生的Hoxa5的条件等位基因，我们表明Hoxa5的条件性缺失 在出生时开始的肺间充质中，导致出生后肺泡简化表型。 Hox5突变动物表现出异常的肌成纤维细胞形态和受损的功能。Hox5突变体 成纤维细胞表现出细胞粘附缺陷，整合素β 5和β 1的表达下降， 监管.令人惊讶的是，Hox 5功能在所有阶段的持续重要性被强调。 初步证据表明，Hoxa5的删除在后期阶段（建立弹性蛋白为基础的 基质）导致弹性蛋白基质完整性的快速丧失。在这个提议中，我们将审问 Hox 5调控肺泡灌洗液中肺间质的细胞和分子机制 发育重塑和体内平衡

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.