ECM Proteomics in lung fibrosis

肺纤维化中的 ECM 蛋白质组学

• 批准号: 10529321
• 负责人: Oliver Eickelberg
• 金额: $ 62.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10529321
• 关键词: 3-Dimensional; Affect; Architecture; Area; Asthma; Atlases; Biological Models; Bleomycin; Cell Communication; Cell Differentiation process; Cell Reprogramming; Cell physiology; Cells; Characteristics; Chemicals; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Cicatrix; Complex; Control Animal; Cues; Data Set; Deposition; Detergents; Development; Digestion; Disease; Enzymes; Epithelial Cells; Epithelium; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Family; Fibroblasts; Fibrosis; Functional disorder; Genes; Glutaminase; Goals; Histologic; Homeostasis; Human; Impairment; Injury; Interstitial Lung Diseases; Knock-out; Knowledge; Label; Lesion; Lung; Maps; Mass Spectrum Analysis; Mediating; Mesenchymal; Methods; Modeling; Molecular; Molecular Conformation; Mus; Natural regeneration; Normal Statistical Distribution; Pattern; Peripheral; Persons; Population; Proteins; Proteome; Proteomics; Pulmonary Fibrosis; Pulmonary Pathology; Pulmonology; Site; Solubility; Structure; Structure of parenchyma of lung; Technology; Testing; Therapeutic; Type II Epithelial Receptor Cell; alveolar epithelium; cell type; crosslink; defined contribution; enzyme activity; genetic approach; idiopathic pulmonary fibrosis; improved; in vivo; injured; insight; knock-down; lung allograft; lung development; lung regeneration; man; new technology; next generation; novel; novel therapeutics; pharmacologic; prototype; regenerative approach; small hairpin RNA; three-dimensional modeling; tissue regeneration; transcriptome sequencing; transglutaminase 2

PROJECT SUMMARY/ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal chronic lung disease, affecting over 5 million people worldwide. To date, there are no therapies that effectively stop progression or reverse the disease. IPF is characterized by altered cellular composition and dysfunction of epithelial-mesenchymal interaction in the peripheral lung, leading to excessive accumulation of extracellular matrix (ECM) and progressive scarring. The IPF lung is characterized by a heterogeneous distribution of normal or mildly affected regions, alternating with regions of significant fibrosis containing septal thickening, honeycombing, aberrant epithelial reprogramming, and fibroblastic foci. Since homeostasis and regeneration of the human lung after injury is controlled by delicate interplay between the ECM and multiple resident cell populations, it is imperative to define the sequential contributions of enhanced ECM secretion and crosslinking on cellular functions. Hence, the definition of the sequential hierarchy of enhanced ECM composition or stiffness obtained by crosslinking enzyme activity on resident lung cell function will enable the identification of precise therapeutic angles for IPF. The overarching goal of this application is to define the composition and crosslinking pattern of the fibrotic ECM, to assess the contribution of fibroblasts to the fibrotic ECM, to mechanistically interrogate the contribution of a prototypic crosslinking enzyme, transglutaminase (TGM) 2, to the above, and to assess its reciprocal effect on alveolar epithelial cell function. We hypothesize that IPF ECM exhibits specific changes and cues, produced by resident fibroblasts and generated by TGM2-dependent crosslinks, which in turn alter lung epithelial cell function and reprogramming. To pursue this hypothesis, we propose a cascade of specific aims: In Aim1, we will utilize a novel proteomics approach in order to define, quantify, and validate, in the greatest possible detail and accuracy, changes in the composition and architecture of the ECM in lung fibrosis by quantifying its composition and crosslinking patterns. In Aim 2, we propose to identify the ECM secreted by control and IPF primary fibroblasts and determine the effect of fibroblast-derived TGM2 on ECM composition and crosslinking. In Aim 3, we will investigate whether and how fibroblast-derived TGM2 affects development of lung fibrosis and ATII cell reprogramming. This proposal is based on the new concept that resident lung cell fate is reciprocally determined by the (fibrotic) ECM. The proposed project will provide unprecedented detail and novel insights into ECM composition and crosslinking patterns in the normal and fibrotic human lung. We will generate novel knowledge on ECM-cell interaction with respect to resident lung cell function and tissue regeneration in IPF. The project will explore a major under-investigated area in lung pathologies and provide substantial groundwork for the development of novel therapies for IPF, which likely will extend to other chronic lung diseases driven by changes in ECM composition, such as asthma, chronic lung allograft dysfunction, or COPD.

项目总结/文摘

项目成果

Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics.

人类纤维化模型中的表型药物筛选确定了一类新型的抗纤维化疗法。

• DOI: 10.1126/sciadv.abb3673
• 发表时间: 2021-12-24
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Gerckens M;Schorpp K;Pelizza F;Wögrath M;Reichau K;Ma H;Dworsky AM;Sengupta A;Stoleriu MG;Heinzelmann K;Merl-Pham J;Irmler M;Alsafadi HN;Trenkenschuh E;Sarnova L;Jirouskova M;Frieß W;Hauck SM;Beckers J;Kneidinger N;Behr J;Hilgendorff A;Hadian K;Lindner M;Königshoff M;Eickelberg O;Gregor M;Plettenburg O;Yildirim AÖ;Burgstaller G
• 通讯作者: Burgstaller G

Integrative analysis of cell state changes in lung fibrosis with peripheral protein biomarkers.

• DOI: 10.15252/emmm.202012871
• 发表时间: 2021-04-09
• 期刊: EMBO molecular medicine
• 影响因子: 11.1
• 作者: Mayr CH;Simon LM;Leuschner G;Ansari M;Schniering J;Geyer PE;Angelidis I;Strunz M;Singh P;Kneidinger N;Reichenberger F;Silbernagel E;Böhm S;Adler H;Lindner M;Maurer B;Hilgendorff A;Prasse A;Behr J;Mann M;Eickelberg O;Theis FJ;Schiller HB
• 通讯作者: Schiller HB

FK506-Binding Protein 11 Is a Novel Plasma Cell-Specific Antibody Folding Catalyst with Increased Expression in Idiopathic Pulmonary Fibrosis.

FK506结合蛋白11是一种新型的浆细胞特异性抗体折叠催化剂，在特发性肺纤维化中的表达增加。

• DOI: 10.3390/cells11081341
• 发表时间: 2022-04-14
• 期刊: CELLS
• 影响因子: 6
• 作者: Preisendoerfer, Stefan;Ishikawa, Yoshihiro;Hennen, Elisabeth;Winklmeier, Stephan;Schupp, Jonas C.;Knueppel, Larissa;Fernandez, Isis E.;Binzenhofer, Leonhard;Flatley, Andrew;Juan-Guardela, Brenda M.;Ruppert, Clemens;Guenther, Andreas;Frankenberger, Marion;Hatz, Rudolf A.;Kneidinger, Nikolaus;Behr, Jurgen;Feederle, Regina;Schepers, Aloys;Hilgendorff, Anne;Kaminski, Naftali;Meinl, Edgar;Baechinger, Hans Peter;Eickelberg, Oliver;Staab-Weijnitz, Claudia A.
• 通讯作者: Staab-Weijnitz, Claudia A.

microRNA Expression Profile of Purified Alveolar Epithelial Type II Cells.

• DOI: 10.3390/genes13081420
• 发表时间: 2022-08-10
• 期刊: GENES
• 影响因子: 3.5
• 作者: Dehmel, Stefan;Weiss, Katharina J.;El-Merhie, Natalia;Callegari, Jens;Konrad, Birte;Mutze, Kathrin;Eickelberg, Oliver;Konigshoff, Melanie;Krauss-Etschmann, Susanne
• 通讯作者: Krauss-Etschmann, Susanne