Mechanisms of epithelial repair and remodeling in pulmonary fibrosis

肺纤维化上皮修复与重塑机制

• 批准号: 10646242
• 负责人: Jonathan Andrew Kropski
• 金额: $ 55.07万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646242
• 关键词: 3-Dimensional; Acute; Air; Alleles; Alveolar; Atypical hyperplasia; Automobile Driving; Basal Cell; Bleomycin; CRISPR/Cas technology; Cell Differentiation process; Cell physiology; Cells; Chronic; Clinical; Data; Disease; Distal; Dose; Epithelial Cells; Epithelium; Exhibits; Extracellular Matrix; Family; Family Study; Fibrosis; G-Protein-Coupled Receptors; Gene Expression; Genes; Genetic; Genomic approach; Human; Human Cell Line; Influenza; Injury; Interstitial Pneumonia; Liquid substance; Lung; Lung diseases; Modeling; Mus; Mutation; Organoids; Orphan; Pathogenesis; Pathologic; Pathway interactions; Patients; Peripheral; Play; Population; Predisposition; Proliferating; Pulmonary Fibrosis; Regulation; Role; Series; Structure of parenchyma of lung; Syndrome; System; Testing; Tracheal Epithelium; Transgenic Mice; Transgenic Organisms; Work; airway epithelium; alveolar epithelium; cell type; comparison control; directed differentiation; epithelial repair; epithelium regeneration; exome sequencing; experimental study; fibrotic lung; in vivo; induced pluripotent stem cell; innovation; loss of function; mutant; novel; programs; rare variant; receptor; repaired; risk variant; segregation; single-cell RNA sequencing; stem cell model; time use

Abstract Pulmonary fibrosis (PF) is a clinical syndrome that represents the end-stage of chronic parenchymal lung diseases. Dysfunctional repair of the distal lung epithelium has been hypothesized as central to PF pathogenesis, but the mechanisms governing epithelial repair following injury remain incompletely understood. In order to comprehensively profile the cell types and gene expression programs driving PF, we performed single-cell RNA-sequencing (scRNA-seq) of peripheral tissue from PF and control lungs and identified dramatic changes in cell types, states, and expression programs in PF lung epithelium including a previously undescribed KRT5-/KRT17+ “distal basal cell” (DBC) population that produces pathologic extracellular matrix. Independently, using whole-exome sequencing for genetic discovery in families with pulmonary fibrosis (Familial Interstitial Pneumonia, FIP), we identified rare mutations in an orphan G-protein coupled receptor (GPR87) that segregate with disease, implicating GPR87 as a novel FIP risk gene. Our preliminary data indicate that GPR87 gene expression is dramatically increased in lung tissue from patients with sporadic cases of IPF, and localizes specifically to these newly described pathologic ECM-producing DBCs. In mice, as in humans, Gpr87 expression was low in the peripheral lung; however, expression increases substantially after following bleomycin injury, where it localized to distal basal cells. We generated mice expressing an FIP- associated mutant form of Gpr87 using a CRISPR-Cas9 gene editing strategy and found that mice carrying a single-copy of the mutation (Gpr87mut/wt) had increased lung fibrosis compared to control mice following a single-dose bleomycin. Unchallenged mice carrying biallelic mutations (Gpr87mut/mut) develop spontaneous airway epithelial remodeling and striking atypical hyperplasia in vivo. Consistent with these findings, culture of Gpr87mut/mut mouse tracheal epithelial cells (MTECs) in air-liquid interface (ALI) and 3D organoid systems resulted in aberrant epithelial differentiation. Together, our preliminary data implicate DBCs in PF pathogenesis and suggest that GPR87 regulates the fate and function of these cells. Our hypothesis is that GPR87 regulates proliferation and differentiation of distal basal cells, which are required for efficient repair of alveolar epithelium after severe or repetitive injury. Our specific aims are: 1) Determine the role of Gpr87- expressing distal basal cells in promoting lung fibrosis. 2) Identify mechanisms regulating distal basal cell fate and function in severe and chronic alveolar injury. 3) Investigate GPR87-dependent regulation of basal cell function and differentiation. In studies proposed below, we will use innovative transgenic mouse, organoid and inducible pluripotent stem cell (iPSC)-based models to investigate the mechanisms through which GPR87 contributes to fibrotic susceptibility and adaptive versus pathologic lung epithelial repair.

摘要

项目成果

Approach to Clinical Trials for the Prevention of Pulmonary Fibrosis.

预防肺纤维化的临床试验方法。

• DOI: 10.1513/annalsats.202303-188ps
• 发表时间: 2023
• 期刊: Annals of the American Thoracic Society
• 影响因子: 8.3
• 作者: Kim,JohnS;Montesi,SydneyB;Adegunsoye,Ayodeji;Humphries,StephenM;Salisbury,MargaretL;Hariri,LidaP;Kropski,JonathanA;Richeldi,Luca;Wells,AtholU;Walsh,Simon;Jenkins,RGisli;Rosas,Ivan;Noth,Imre;Hunninghake,GaryM;Martinez,
• 通讯作者: Martinez,

Myeloid Cell Derived IL1β Contributes to Pulmonary Vascular Remodeling in Heart Failure with Preserved Ejection Fraction.

骨髓细胞衍生的 IL1β 有助于心力衰竭的肺血管重塑，并保留射血分数。

• DOI: 10.1101/2023.05.18.541302
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Agrawal,Vineet;Kropski,JonathanA;Gokey,JasonJ;Kobeck,Elizabeth;Murphy,Matthew;Murray,KatherineT;Fortune,NikiL;Moore,ChristyS;Meoli,DavidF;Monahan,Ken;Su,YanRu;Blackwell,Thomas;Gupta,DeepakK;Talati,MeghaH;Gladson,Santh
• 通讯作者: Gladson,Santh

Idiopathic pulmonary fibrosis: Disease mechanisms and drug development.

• DOI: 10.1016/j.pharmthera.2020.107798
• 发表时间: 2021-06
• 期刊: Pharmacology & therapeutics
• 影响因子: 13.5
• 作者: Spagnolo P;Kropski JA;Jones MG;Lee JS;Rossi G;Karampitsakos T;Maher TM;Tzouvelekis A;Ryerson CJ
• 通讯作者: Ryerson CJ

The Role of Hippo/YAP Signaling in Alveolar Repair and Pulmonary Fibrosis.

• DOI: 10.3389/fmed.2021.752316
• 发表时间: 2021
• 期刊: Frontiers in medicine
• 影响因子: 3.9
• 作者: Gokey JJ;Patel SD;Kropski JA
• 通讯作者: Kropski JA

Thromboxane-Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis.

血栓素-前列腺素受体信号传导驱动肺纤维化中成纤维细胞的持续激活。

• DOI: 10.1164/rccm.202106-1503oc
• 发表时间: 2022
• 期刊: American journal of respiratory and critical care medicine
• 影响因子: 24.7
• 作者: Suzuki,Toshio;Kropski,JonathanA;Chen,Jingyuan;Carrier,EricaJ;Chen,Xinping;Sherrill,TaylorP;Winters,NichelleI;Camarata,JaneE;Polosukhin,VasiliyV;Han,Wei;Rathinasabapathy,Anandharajan;Gutor,Sergey;Gulleman,Peter;Sabusap,Carl
• 通讯作者: Sabusap,Carl