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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

基本信息

批准号：
9980992
负责人：
Deneen M Wellik
金额：
$ 44.14万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980992
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 Respiratory physiology 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 transcription factor transcriptome sequencing

项目摘要

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.

抽象的肺泡发生发生在人类和小鼠的出生后发育过程中，这个过程允许用于增加肺部气体交换表面积。这一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基质。将弹性蛋白掺入现有的肺基质提供弹性，使远端气道有效地伸展和回缩呼吸过程中，中胚层来源的 SMA+ 肺成纤维细胞是这一过程的关键驱动因素。我们的先前发表的研究表明，Hox5 基因仅在肺间充质以及所有三个 Hox5 基因的缺失会导致早期、严重的发育障碍肺部缺陷和新生儿死亡。四等位基因、复合 Hox5 突变小鼠 (Hox5 AabbCc) 出生于孟德尔比率和出生时表型正常，然而，它们在产后阶段。与 Hox5 基因在肺泡发生中的直接作用一致，表达水平所有三个 Hox5 基因在产后早期阶段最高，此时肺泡发生大量发生率高于任何胚胎阶段观察到的水平，并且这些基因在成年后仍保持表达生活。使用新生成的 Hoxa5 条件等位基因，我们表明 Hoxa5 的条件删除出生时开始的肺间充质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功能受损。 Hox5突变体成纤维细胞表现出细胞粘附缺陷，整合素α5和β1的表达下降受监管。令人惊讶的是，Hox5 功能在各个阶段的持续重要性得到了凸显初步证据表明，Hoxa5 在后期（基于弹性蛋白的组织建立后）被删除。基质）导致弹性蛋白基质的完整性迅速丧失。在本提案中，我们将询问 Hox5在肺泡形成过程中调节肺间质的细胞和分子机制发育、重塑和体内平衡。