Maintenance of the alveolar niche in emphysema
肺气肿肺泡微环境的维护
基本信息
- 批准号:9768539
- 负责人:
- 金额:$ 46.25万
- 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:2018-08-22 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAllelesAlveolarAnatomyAppearanceAttenuatedBehaviorBindingBiological AssayCell CompartmentationCell surfaceCellsChronic lung diseaseClinicalComplexDataDevelopmentDifferentiation and GrowthDiseaseDistalEpithelialErinaceidaeFDA approvedFeedbackGasesGenesGeneticGenetic Predisposition to DiseaseGenetic studyHistologicHomeostasisHumanIn VitroKnowledgeLeadLinkLungLung diseasesMaintenanceMitogensModelingMusNatureOrganoidsPathogenicityPathway interactionsPatientsPopulationPre-Clinical ModelProteinsProteomicsPulmonary EmphysemaReporterRoleSHH geneSamplingSpecimenStem cellsStructureSurfaceSusceptibility GeneTestingTherapeuticVariantgenome wide association studyhuman diseaseinhibitor/antagonistinsightnovelprogenitorreconstitutionsegregationsingle cell analysissingle-cell RNA sequencingsmoothened signaling pathwaystemtooltranscriptometranscriptomics
项目摘要
Project Summary/Abstract
The lung possesses multiple stem/progenitor compartments along the proximal-distal axis where the
epithelial stem/progenitors are situated in close proximity to the underlying stroma. Despite their
homogeneity in appearance, it is increasingly apparent that the lung stroma contains diverse subsets,
each uniquely suited to maintain the nearest stem/progenitor population. Thus, the current gap in
knowledge is not whether stromal compartments are diverse, but rather how segregated stromal
identities are maintained in different niches, and how disruption of distinct stromal identity can lead to
disease. Utilizing a combination of single cell RNA-sequencing and a unique mouse genetic tool we built
to isolate the stroma, our preliminary data demonstrate that hedgehog (Hh) activation promotes proximal
stromal genes while suppressing genes associated with the distal alveolar stroma. Furthermore, distal
expansion of Hh activation in the alveolar stroma attenuates stromal mitogen feedback to the alveolar
stem/progenitors, leading to alveolar loss comparable to emphysema. Relevant to human disease,
genome-wide association studies (GWASes) have identified numerous susceptibility loci for emphysema
near the gene for Hedgehog-interacting protein (HHIP), a negative regulator of Hh activation, but
mechanistic studies to define the pathogenic association have been lacking. Our central hypothesis is
that HHIP, a negative regulator of SHH binding, restricts Hh activation to the proximal stroma to maintain
proximal-distal segregation of stromal identity, the loss of which leads to disruption of the alveolar
stem/progenitor niche and loss of alveoli comparable to emphysema. Leveraging the novel mouse
genetic tools we have developed, our single cell analysis, and our access to clinical specimen, this
proposal aims to address how stromal subsets maintain their distinct identity during normal homeostasis,
how Hh alters the stromal feedback to the alveolar stem/progenitors, and how disruption of the alveolar
niche can lead to chronic lung diseases such as emphysema.
项目概要/摘要
肺沿着近端-远端轴拥有多个干/祖室,其中
上皮干/祖细胞位于靠近底层基质的位置。尽管他们的
外观上的同质性,越来越明显的是,肺基质包含不同的子集,
每个都独特地适合维持最近的干细胞/祖细胞群体。因此,目前的差距
知识不是基质隔室是否多样化,而是基质如何分离
身份在不同的生态位中保持,以及不同基质身份的破坏如何导致
疾病。结合单细胞 RNA 测序和我们构建的独特小鼠遗传工具
为了分离基质,我们的初步数据表明刺猬 (Hh) 激活促进近端
基质基因,同时抑制与远端肺泡基质相关的基因。此外,远端
肺泡基质中 Hh 激活的扩展减弱了基质丝裂原对肺泡的反馈
干/祖细胞,导致与肺气肿相当的肺泡损失。与人类疾病相关,
全基因组关联研究 (GWAS) 已确定了许多肺气肿的易感位点
靠近刺猬相互作用蛋白 (HHIP) 的基因,HHIP 是 Hh 激活的负调节因子,但是
缺乏确定致病关联的机制研究。我们的中心假设是
HHIP 是 SHH 结合的负调节因子,将 Hh 激活限制在近端基质以维持
基质特性的近端-远端分离,其丧失导致肺泡破坏
干/祖细胞生态位和肺泡损失与肺气肿相当。利用新颖的鼠标
我们开发的遗传工具、我们的单细胞分析以及我们对临床样本的获取,这
该提案旨在解决基质亚群如何在正常稳态期间保持其独特的身份,
Hh 如何改变对肺泡干/祖细胞的基质反馈,以及如何破坏肺泡
生态位可导致慢性肺部疾病,例如肺气肿。
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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Tien Peng其他文献
Tien Peng的其他文献
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{{ truncateString('Tien Peng', 18)}}的其他基金
Deciphering the role of p16INK4A+ fibroblasts in lung fibrosis
解读 p16INK4A 成纤维细胞在肺纤维化中的作用
- 批准号:
10340480 - 财政年份:2022
- 资助金额:
$ 46.25万 - 项目类别:
Deciphering the role of p16INK4A+ fibroblasts in lung fibrosis
解读 p16INK4A 成纤维细胞在肺纤维化中的作用
- 批准号:
10559515 - 财政年份:2022
- 资助金额:
$ 46.25万 - 项目类别:
Mesenchymal modulation of epithelial metaplasia in lung fibrosis
肺纤维化中上皮化生的间充质调节
- 批准号:
10548148 - 财政年份:2021
- 资助金额:
$ 46.25万 - 项目类别:
Mesenchymal modulation of epithelial metaplasia in lung fibrosis
肺纤维化中上皮化生的间充质调节
- 批准号:
10331772 - 财政年份:2021
- 资助金额:
$ 46.25万 - 项目类别:
Mesenchymal modulation of epithelial metaplasia in lung fibrosis
肺纤维化中上皮化生的间充质调节
- 批准号:
10095587 - 财政年份:2021
- 资助金额:
$ 46.25万 - 项目类别:
The roles of Hedgehog signaling in pulmonary vascular development and remodeling
Hedgehog信号在肺血管发育和重塑中的作用
- 批准号:
9118452 - 财政年份:2014
- 资助金额:
$ 46.25万 - 项目类别:
The roles of Hedgehog signaling in pulmonary vascular development and remodeling
Hedgehog信号在肺血管发育和重塑中的作用
- 批准号:
9300965 - 财政年份:2014
- 资助金额:
$ 46.25万 - 项目类别:
The roles of Hedgehog signaling in pulmonary vascular development and remodeling
Hedgehog信号在肺血管发育和重塑中的作用
- 批准号:
8766755 - 财政年份:2014
- 资助金额:
$ 46.25万 - 项目类别:
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