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:
- 金额:$ 44.14万
- 依托单位:
- 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:
- 关键词:AdhesionsAdultAllelesAlveolarAnimalsAreaAutomobile DrivingBasement membraneBehaviorBiologyBirthBreathingBronchopulmonary DysplasiaCell AdhesionChIP-seqCollagenComplexDataDefectDevelopmentDiseaseDistalDoxycyclineElasticityElastinEmbryoEventExhibitsExtracellular MatrixFamilyFibroblastsFibronectinsGasesGene ExpressionGene Expression RegulationGenerationsGenesGeneticGrowthHomeostasisHumanITGA5 geneImpairmentIn VitroIntegrinsKnock-inKnowledgeLeadLifeLoxP-flanked alleleLungLung ComplianceMaintenanceMechanicsMediatingMesenchymalMesenchymeMesodermMolecularMorphologyMusMutant Strains MiceMyofibroblastPathway interactionsPatientsPhasePhenotypeProcessPublishingPulmonary EmphysemaPulmonary function testsRegulationRespiratory physiologyRoleStretchingStructureStructure of parenchyma of lungSurfaceTestingTherapeuticTissuesWorkbasecell typegene functionidiopathic pulmonary fibrosisin vivointerstitiallung developmentlung volumemouse modelmutantneonatal deathparalogous genepostnatalpostnatal developmentpreventtranscription factortranscriptome 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.
摘要
肺泡发育发生在人类和小鼠的出生后发育期间,这一过程允许
用于生长肺的气体交换表面积。这一阶段的关键事件之一是
远端气道弹性蛋白基质的建立。弹性蛋白被结合到
现有的肺基质提供了弹性,允许远端呼吸道有效地伸展和回缩
在呼吸和中胚层来源的SMA+肺成纤维细胞是这一过程的关键驱动细胞。我们的
先前发表的研究表明,Hox5基因仅在
肺间充质和所有三个Hox5基因的缺失导致早期、严重的发育
肺缺陷和新生儿死亡。四等位基因,复合Hox5突变小鼠(Hox5 AabbCc)出生于
孟德尔比率在出生时是表型正常的,然而,它们在出生时发展为肺泡简化
出生后阶段。符合Hox5基因在肺泡发育中的直接作用,表达水平
在所有三个Hox5基因中,Hox5基因在出生后早期阶段最高,此时大部分肺泡发育
发生,比在任何胚胎阶段观察到的要高,这些基因在成年后仍保持表达
生活。使用新产生的Hoxa5的条件等位基因,我们发现Hoxa5的条件缺失
在肺中,出生时开始的间质在出生后导致肺泡简化表型。
Hox5基因突变的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
成纤维细胞存在细胞黏附缺陷,整合素5和1表达下调。
受监管的。令人惊讶的是,Hox5功能在所有阶段都继续发挥着重要作用
初步证据表明,在后期(以弹性蛋白为基础的建立之后)Hoxa5的缺失
基质)导致弹性蛋白基质的完整性迅速丧失。在这份提案中,我们将审问
Hox5在肺泡发育过程中调节肺间充质的细胞和分子机制
发展、重塑和动态平衡。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Deneen M Wellik其他文献
Deneen M Wellik的其他文献
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{{ truncateString('Deneen M Wellik', 18)}}的其他基金
Hox-Regulated MSCs in Skeletal Development, Growth and Fracture Healing
Hox 调节的 MSC 在骨骼发育、生长和骨折愈合中的作用
- 批准号:
10566127 - 财政年份:2022
- 资助金额:
$ 44.14万 - 项目类别:
Hox-Regulated MSCs in Skeletal Development, Growth and Fracture Healing
Hox 调节的 MSC 在骨骼发育、生长和骨折愈合中的作用
- 批准号:
10840553 - 财政年份:2022
- 资助金额:
$ 44.14万 - 项目类别:
Hox-Regulated MSCs in Skeletal Development, Growth and Fracture Healing
Hox 调节的 MSC 在骨骼发育、生长和骨折愈合中的作用
- 批准号:
10662574 - 财政年份:2022
- 资助金额:
$ 44.14万 - 项目类别:
Hox genes regulate functionally distinct, regionally restricted MSC populations
Hox 基因调节功能不同、区域受限的 MSC 群体
- 批准号:
10197314 - 财政年份:2019
- 资助金额:
$ 44.14万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 44.14万 - 项目类别:
Hox-Expressing Stromal Cells in Muscle Development and Repair
表达 Hox 的基质细胞在肌肉发育和修复中的作用
- 批准号:
9530540 - 财政年份:2017
- 资助金额:
$ 44.14万 - 项目类别:
Using BMSC-derived Bone-Ligament-Bone Tissue as a Live Template for ACL Regenerat
使用 BMSC 衍生的骨韧带骨组织作为 ACL 再生的实时模板
- 批准号:
8490317 - 财政年份:2012
- 资助金额:
$ 44.14万 - 项目类别:
Using BMSC-derived Bone-Ligament-Bone Tissue as a Live Template for ACL Regenerat
使用 BMSC 衍生的骨韧带骨组织作为 ACL 再生的实时模板
- 批准号:
8383131 - 财政年份:2012
- 资助金额:
$ 44.14万 - 项目类别:
Role of Hox Genes in Integration of the Musculoskeletal System in Development
Hox 基因在发育中肌肉骨骼系统整合中的作用
- 批准号:
8308416 - 财政年份:2011
- 资助金额:
$ 44.14万 - 项目类别:
Role of Hox Genes in Integration of the Musculoskeletal System in Development
Hox 基因在发育中肌肉骨骼系统整合中的作用
- 批准号:
8840889 - 财政年份:2011
- 资助金额:
$ 44.14万 - 项目类别:
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