Maintenance of the alveolar niche in emphysema

肺气肿肺泡微环境的维护

• 批准号: 10435711
• 负责人: Tien Peng
• 金额: $ 13.06万
• 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/10435711
• 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得以维持，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 Hedgehog 相互作用蛋白 (HHIP) 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 生态位可导致肺气肿等慢性肺部疾病。

项目成果

Intersection of Inflammation and Senescence in the Aging Lung Stem Cell Niche.

衰老肺干细胞生态位中炎症和衰老的交叉点。

• 发表时间: 2022
• 作者: Allen, Nancy C;Reyes, Nabora S;Lee, Jin Young;Peng, Tien
• 通讯作者: Peng, Tien

Dysregulated lung stroma drives emphysema exacerbation by potentiating resident lymphocytes to suppress an epithelial stem cell reservoir.

肺基质失调通过增强驻留淋巴细胞抑制上皮干细胞库而导致肺气肿恶化。

• 发表时间: 2023-03-14
• 影响因子: 32.4
• 作者: Wang, Chaoqun;Hyams, Ben;Allen, Nancy C;Cautivo, Kelly;Monahan, Kiara;Zhou, Minqi;Dahlgren, Madelene W;Lizama, Carlos O;Matthay, Michael;Wolters, Paul;Molofsky, Ari B;Peng, Tien
• 通讯作者: Peng, Tien

Bad Neighbors or Bad Neighborhoods: Pathogenic Residency of T Cells in Chronic Obstructive Pulmonary Disease.

坏邻居或坏邻居：慢性阻塞性肺疾病中 T 细胞的致病性驻留。

• 发表时间: 2023-12-01
• 影响因子: 24.7
• 作者: Peng; Tien
• 通讯作者: Tien

An inflammatory switch for stem cell plasticity.

干细胞可塑性的炎症开关。

• 发表时间: 2021
• 影响因子: 21.3
• 作者: Kathiriya, Jaymin J;Peng, Tien
• 通讯作者: Peng, Tien

Sentinel p16INK4a+ cells in the basement membrane form a reparative niche in the lung.

基底膜中的前哨 p16INK4a 细胞在肺中形成修复生态位。

• 发表时间: 2022-10-14
• 作者: Reyes, Nabora S;Krasilnikov, Maria;Allen, Nancy C;Lee, Jin Young;Hyams, Ben;Zhou, Minqi;Ravishankar, Supriya;Cassandras, Monica;Wang, Chaoqun;Khan, Imran;Matatia, Peri;Johmura, Yoshikazu;Molofsky, Ari;Matthay, Michael;Nakanishi, Makoto;Shep
• 通讯作者: Shep