Maintenance of the alveolar niche in emphysema

肺气肿肺泡微环境的维护

• 批准号: 10208941
• 负责人: Tien Peng
• 金额: $ 54.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10208941
• 关键词: Address; Alleles; Alveolar; Anatomy; Appearance; Attenuated; Behavior; Binding; Biological Assay; Cell Compartmentation; Cell surface; Cells; Chronic lung disease; Clinical; Complex; Data; Development; Differentiation and Growth; Disease; Distal; Epithelial; Erinaceidae; FDA approved; Feedback; Gases; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Histologic; Homeostasis; Human; In Vitro; Knowledge; Lead; Link; Lung; Lung diseases; Maintenance; Mitogens; Modeling; Nature; Organoids; Pathogenicity; Pathway interactions; Patients; Population; Pre-Clinical Model; Proteins; Proteomics; Pulmonary Emphysema; Reporter; Role; SHH gene; Sampling; Specimen; Structure; Surface; Susceptibility Gene; Testing; Therapeutic; Variant; genome wide association study; human disease; inhibitor/antagonist; insight; mouse genetics; novel; progenitor; reconstitution; segregation; single cell analysis; single-cell RNA sequencing; smoothened signaling pathway; stem; stem cells; tool; transcriptome; transcriptomics

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.

项目摘要/摘要 肺沿着近端轴具有多个茎/祖细胞室，其中 上皮茎/祖细胞位于靠近基质的附近。尽管他们 外观同质性，越来越明显的是，肺基质包含多种多样的子集， 每个独特的适合维持最近的茎/祖先种群。因此，当前差距 知识不是基质隔室是否多样化，而是隔离的基础 身份保持在不同的小境中，以及不同的基质身份的破坏如何导致 疾病。利用单细胞RNA测序和我们构建的独特鼠标遗传工具的组合 为了隔离基质，我们的初步数据表明刺猬（HH）激活促进了近端 基质基因抑制与远端肺泡基质相关的基因。此外，远端 肺泡基质中HH激活的膨胀减弱了基质有丝分裂原反馈到肺泡 茎/祖细胞，导致牙槽损失与肺气肿相当。与人类疾病有关 全基因组关联研究（GWASE）已经确定了肺气肿的许多敏感性基因座 在刺猬相互作用蛋白（HHIP）的基因附近，HH激活的负调节剂，但 缺乏定义致病关联的机械研究。我们的中心假设是 HHIP是SHH结合的负调节剂，将HH激活限制为近端基质以维持 基质身份的近端分离，其损失导致肺泡破坏 茎/祖细胞生态位和肺泡的损失与肺气肿相当。利用新颖的老鼠 我们开发的遗传工具，单细胞分析以及我们获得临床标本的访问 建议旨在解决基质子集如何在正常体内稳态期间保持其独特的身份， HH如何改变基质对肺泡茎/祖细胞的反馈，以及肺泡的破坏 利基市场可以导致慢性肺部疾病，例如肺气肿。