ECM Proteomics in lung fibrosis

肺纤维化中的 ECM 蛋白质组学

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要特发性肺纤维化 (IPF) 是一种进行性且致命的慢性肺部疾病，影响超过 500 万人全世界。迄今为止，尚无有效阻止疾病进展或逆转疾病的疗法。特发性肺纤维化是其特征是细胞组成改变和上皮间质相互作用功能障碍周围肺，导致细胞外基质（ECM）过度积累和进行性疤痕形成。这 IPF 肺部的特点是正常或轻度受影响区域的异质分布，与显着纤维化区域，包括间隔增厚、蜂窝状、异常上皮重编程、和成纤维细胞灶。由于受伤后人肺的稳态和再生是由微妙的控制的由于 ECM 和多个常驻细胞群之间的相互作用，必须定义顺序增强的 ECM 分泌和交联对细胞功能的贡献。因此，定义通过交联酶活性获得的增强 ECM 成分或刚度的连续层次结构常驻肺细胞功能将能够确定 IPF 的精确治疗角度。首要的该应用的目标是定义纤维化 ECM 的成分和交联模式，以评估成纤维细胞对纤维化 ECM 的贡献，以机械方式询问其贡献原型交联酶转谷氨酰胺酶 (TGM) 2 与上述的关系，并评估其倒数对肺泡上皮细胞功能的影响。我们假设 IPF ECM 表现出特定的变化和线索，由常驻成纤维细胞产生并由 TGM2 依赖性交联产生，进而改变肺上皮细胞细胞功能和重编程。为了实现这一假设，我们提出了一系列具体目标：在 Aim1 中，我们将利用一种新颖的蛋白质组学方法来尽可能地定义、量化和验证通过量化肺纤维化中 ECM 的组成和结构的细节和准确性组成和交联模式。在目标 2 中，我们建议识别控制和 IPF 分泌的 ECM 原代成纤维细胞并确定成纤维细胞衍生的 TGM2 对 ECM 组成和交联的影响。在目标 3 中，我们将研究成纤维细胞衍生的 TGM2 是否以及如何影响肺纤维化和肺纤维化的发展。 ATII 细胞重编程。该提议基于常驻肺细胞命运是相互的新概念由（纤维化）ECM 确定。拟议的项目将提供前所未有的细节和新颖的见解正常和纤维化人肺中的 ECM 组成和交联模式。我们将生成小说关于 IPF 中常驻肺细胞功能和组织再生的 ECM-细胞相互作用的知识。这该项目将探索肺部病理学中一个主要的未充分研究领域，并为以下方面提供实质性基础：针对 IPF 的新疗法的开发，可能会扩展到由以下原因引起的其他慢性肺部疾病 ECM 成分发生变化，例如哮喘、慢性肺同种异体移植功能障碍或 COPD。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lung Epithelium Releases Growth Differentiation Factor 15 in Response to Pathogen-mediated Injury.

肺上皮释放生长分化因子 15 以应对病原体介导的损伤。

DOI：
发表时间：
2024-02-01
期刊：
影响因子：
6.4
作者：
Shah, Faraaz A;Bahudhanapati, Harinath;Jiang, Mao;Tabary, Mohammadreza;van der Geest, Rick;Tolman, Nathanial J;Kochin, Megan;Xiong, Zeyu;Al;Sayed, Khaled;Benos, Panayiotis V;Raffensperger, Kristen;Evankovich, John;Neal, Matthew
通讯作者：
Neal, Matthew

National Heart, Lung, and Blood Institute and Building Respiratory Epithelium and Tissue for Health (BREATH) Consortium Workshop Report: Moving Forward in Lung Regeneration.

国家心肺血液研究所和健康呼吸上皮和组织 (BREATH) 联盟研讨会报告：肺再生的进展。

DOI：
发表时间：
2021-07
期刊：
影响因子：
6.4
作者：
Hynds, Robert E;Zacharias, William J;Nikolić, Marko Z;Königshoff, Melanie;Eickelberg, Oliver;Gosens, Reinoud;de Coppi, Paolo;Janes, Sam M;Morrisey, Edward;Clevers, Hans;Ryan, Amy L;Stripp, Barry R;Sun, Xin;Kim, Carla F;Lin, Qing S
通讯作者：
Lin, Qing S

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 是一种新型浆细胞特异性抗体折叠催化剂，在特发性肺纤维化中表达增加。

DOI：
发表时间：
2022-04-14
期刊：
影响因子：
6
作者：
Preisendörfer, Stefan;Ishikawa, Yoshihiro;Hennen, Elisabeth;Winklmeier, Stephan;Schupp, Jonas C;Knüppel, Larissa;Fernandez, Isis E;Binzenhöfer, Leonhard;Flatley, Andrew;Juan;Ruppert, Clemens;Guenther, Andreas;Frankenberger
通讯作者：
Frankenberger

Listen to the WNT; It Talks: WNT7A Drives Epithelial-Mesenchymal Cross-Talk within the Fibrotic Niche in Idiopathic Pulmonary Fibrosis.

听听WNT；

DOI：
发表时间：
2023-03
期刊：
影响因子：
6.4
作者：
Königshoff, Melanie;Eickelberg, Oliver
通讯作者：
Eickelberg, Oliver

Sfrp1 inhibits lung fibroblast invasion during transition to injury-induced myofibroblasts.

Sfrp1 在向损伤诱导的肌成纤维细胞转变过程中抑制肺成纤维细胞侵袭。

DOI：
发表时间：
2024-02
期刊：
影响因子：
0
作者：
Mayr, Christoph H;Sengupta, Arunima;Asgharpour, Sara;Ansari, Meshal;Pestoni, Jeanine C;Ogar, Paulina;Angelidis, Ilias;Liontos, Andreas;Rodriguez;Lang, Niklas J;Strunz, Maximilian;Porras;Gerckens, Michael
通讯作者：
Gerckens, Michael