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.
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。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Deneen M Wellik其他文献
Deneen M Wellik的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 44.14万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 44.14万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 44.14万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 44.14万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 44.14万 - 项目类别:
Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 44.14万 - 项目类别:
Discovery Early Career Researcher Award
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
- 批准号:
10065645 - 财政年份:2023
- 资助金额:
$ 44.14万 - 项目类别:
Collaborative R&D
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 44.14万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 44.14万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 44.14万 - 项目类别:
Grant-in-Aid for Scientific Research (C)














{{item.name}}会员




