The Fetal Lung Mesothelial Differentiation Program
胎儿肺间皮分化计划
基本信息
- 批准号:8462105
- 负责人:
- 金额:$ 52.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-05 至 2017-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAllelesAllergensAppearanceAreaAsthmaAttenuatedBackBindingBiologyBody cavitiesCell LineCell LineageCellsDataDevelopmentEmbryoEpitheliumErinaceidaeEventFetal LungFibrosisFlow CytometryFoundationsFutureGene ExpressionGenerationsGenesGoalsGrantGreen Fluorescent ProteinsGrowthHarvestHeartImmigrationIndividualInflammationInflammatoryInvestigationKineticsKnock-in MouseLabelLeadLifeLiverLungMediatingMesenchymalMesenchymeMesothelial CellMesotheliumMessenger RNAModelingMusNephroblastomaOrganOvalbuminPathway interactionsPatternPhenotypePlayPloidiesPneumonectomyPrimatesProcessReporterRestRoleRosaSignal TransductionSmooth Muscle MyocytesSquamous CellTamoxifenTestingTimeTissuesTotal Lung CapacityWorkbody cavityfetalinjuredlung developmentlung injurylung repairmigrationmonolayermouse developmentmutantnovelprogenitorprogramspromoterpublic health relevancerecombinaserepairedresearch studyselective expressionsmoothened signaling pathwaytranscription factor
项目摘要
DESCRIPTION (provided by applicant): To what extent mesothelial-derived cells contribute to lung development and post-natal repair is an open and basic question for the field. The objectives of this grant are to address this fundamental issue and to assess the key role of the Wilm's tumor 1 transcription factor (WT1) in these events. Using mouse lines that carry WT1 alleles with a knock-in Cre recombinase and GFP genes, we generated preliminary data leading to 3 hypotheses that will be examined: 1) the fetal mesothelium contains progenitors for differentiated mesenchymal lung cells 2) WT1 controls the expression of key genes, such as hedgehog (Hh) pathway constituents that control mesothelial migration into the fetal lung, and 3) mesothelium-derived cells contribute to post-natal lung repair and re-growth. To summarize, we found that WT1 is selectively expressed in the lung mesothelium from E11.5 to E16 and is undetectable in the adult. We identified a similar temporal pattern of WT1 expression in the primate lung, suggesting a conserved mesothelial WT1 program across mammalian species. Lineage tracing showed that mesothelium-derived cells give rise to a substantial number of bronchial smooth muscle cells (BSM), along with other parenchymal lung cells whose identities will be established (Aim 1). We observed that WT1 expression coincides with mesothelial cell entry into the underlying lung and active Hh signaling. Mechanistically, we found that WT1 binds to the promoters of multiple Hh pathway genes in mesothelial cells, and that selective loss of mesothelial Hh signaling markedly attenuates entry into the underlying lung in association with diminished expression of EMT genes. These data point to a key role for WT1 in the fetal mesothelium, controlling pathways such as Hh signaling that are involved in migration and EMT, which will be further explored (Aim 2). Interestingly, preliminary data indicate that WT1 is reactivated during lung re-growth post-pneumonectomy whereas WT1 is not re-activated in inflammatory lung injuries, such as asthma and fibrosis. These findings suggest 2 models for how the mesothelium may contribute to lung remodeling in post-natal life. In model 1, the fetal WT1-regulated mesothelial program is re-activated. In model 2, parenchymal cells that arise from the fetal mesothelium in development contribute to repair. To what degree these models are involved in lung re- growth and remodeling in post-natal life will be further examined (Aim 3).
We expect that completion of these studies will establish a firm foundation for future work in this
new area of lung biology.
描述(由申请人提供):间皮来源的细胞在多大程度上有助于肺发育和产后修复是该领域的一个开放和基本问题。这项资助的目的是解决这一基本问题,并评估Wilm's肿瘤1转录因子(WT 1)在这些事件中的关键作用。使用携带具有敲入Cre重组酶和GFP基因的WT1等位基因的小鼠品系,我们产生了初步数据,导致将检验的3个假设:1)胎儿间皮细胞含有分化的间充质肺细胞的祖细胞2)WT 1控制关键基因的表达,例如控制间皮细胞迁移到胎儿肺中的刺猬(Hh)途径成分,和3)间皮衍生的细胞有助于出生后肺修复和再生长。总之,我们发现WT1在E11.5至E16期间选择性地在肺间皮中表达,并且在成人中检测不到。我们确定了一个类似的时间模式WT1表达在灵长类动物肺,这表明一个保守的mesothelium WT1程序在哺乳动物物种。谱系追踪显示,间皮来源的细胞产生大量支气管平滑肌细胞(BSM),沿着其他实质肺细胞,其身份将被确定(目的1)。我们观察到WT1表达与间皮细胞进入潜在的肺和活跃的Hh信号传导相一致。从机制上讲,我们发现WT1与间皮细胞中多个Hh通路基因的启动子结合,并且间皮Hh信号的选择性丢失显著减弱了与EMT基因表达减少相关的进入下层肺的能力。这些数据指出了WT1在胎儿间皮中的关键作用,控制诸如参与迁移和EMT的Hh信号传导的途径,这将被进一步探索(目的2)。有趣的是,初步数据表明,WT1在肺切除术后的肺再生过程中被重新激活,而WT1在炎症性肺损伤(如哮喘和纤维化)中没有被重新激活。这些研究结果表明,2模型如何间皮可能有助于肺重塑在出生后的生活。在模型1中,胎儿WT 1调节的间皮细胞程序被重新激活。在模型2中,发育中的胎儿间皮细胞产生的实质细胞有助于修复。将进一步检查这些模型在多大程度上参与出生后生命中的肺再生长和重塑(目的3)。
我们期望这些研究的完成将为今后在这方面的工作奠定坚实的基础。
肺生物学的新领域。
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 }}
Xingbin Ai其他文献
Xingbin Ai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('Xingbin Ai', 18)}}的其他基金
COVID-19 imprints airway basal cells to impair epithelium regeneration
COVID-19 印记气道基底细胞,损害上皮再生
- 批准号:
10738549 - 财政年份:2023
- 资助金额:
$ 52.6万 - 项目类别:
Age-related mechanisms of T helper 2 memory in the early lung
早期肺部辅助T辅助细胞2记忆的年龄相关机制
- 批准号:
10316809 - 财政年份:2021
- 资助金额:
$ 52.6万 - 项目类别:
Age-related mechanisms of T helper 2 memory in the early lung
早期肺部辅助T辅助细胞2记忆的年龄相关机制
- 批准号:
10447694 - 财政年份:2021
- 资助金额:
$ 52.6万 - 项目类别:
Age-related mechanisms of T helper 2 memory in the early lung
早期肺部辅助T辅助细胞2记忆的年龄相关机制
- 批准号:
10653092 - 财政年份:2021
- 资助金额:
$ 52.6万 - 项目类别:
Development of PNEC innervation and neuroplasticity after early life insult
早期生活损伤后 PNEC 神经支配和神经可塑性的发展
- 批准号:
9310524 - 财政年份:2017
- 资助金额:
$ 52.6万 - 项目类别:
Development of PNEC innervation and neuroplasticity after early life insult
早期生活损伤后 PNEC 神经支配和神经可塑性的发展
- 批准号:
10089028 - 财政年份:2017
- 资助金额:
$ 52.6万 - 项目类别:
Identification of Sulfs as therapeutic targets for the treatment of age-impaired skeletal muscle regeneration
确定磺基作为治疗年龄受损骨骼肌再生的治疗靶点
- 批准号:
8918172 - 财政年份:2014
- 资助金额:
$ 52.6万 - 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:
$ 52.6万 - 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:
$ 52.6万 - 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:
$ 52.6万 - 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:
$ 52.6万 - 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:
$ 52.6万 - 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:
$ 52.6万 - 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:
$ 52.6万 - 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:
$ 52.6万 - 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:
$ 52.6万 - 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:
$ 52.6万 - 项目类别:
Grant-in-Aid for Scientific Research (C)