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Wnt-beta-catenin cross interactions in alveolar macrophages and epithelial cells in persistence of SSc-ILD

SSc-ILD 持续存在时肺泡巨噬细胞和上皮细胞中 Wnt-β-连环蛋白的交叉相互作用

基本信息

批准号：
10063540
负责人：
Cara J Gottardi
金额：
$ 73.47万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-22 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063540
关键词：
Ablation Address Adult Alveolar Macrophages Area Asbestos Binding Bleomycin Blood Cells Cellular biology Chemicals Data Development Disease Disease Progression Epithelial Cells Felis catus Fibrosis Gene Expression Profiling Genes Genetic High Prevalence Human Immune System Diseases Immune response Immunoglobulins Injury Interstitial Lung Diseases LDL-Receptor Related Protein 1 Laboratories Lectin Ligands Link Lung Lung diseases Medical Molecular Molecular Target Morbidity - disease rate Mus Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Peripheral Blood Mononuclear Cell Phenotype Play Population Prognosis Pulmonary Fibrosis Reaction Recruitment Activity Resolution Respiratory Failure Role Sampling Sialic Acids Signal Pathway Signal Transduction Systemic Scleroderma Testing Therapeutic Intervention Tissues Transgenic Mice Up-Regulation WNT Signaling Pathway Work alveolar epithelium alveolar type II cell base beta catenin cell type cellular targeting cohort effective therapy idiopathic pulmonary fibrosis improved in vivo injured lung injury lung repair mRNA Expression macrophage monocyte mortality mouse model new therapeutic target receptor recruit repaired sialic acid binding Ig-like lectin tissue injury tissue repair transcriptome

项目摘要

Project summary Systemic sclerosis (SSc) is a progressive fibrotic disease for which there is no effective treatment. Presently, the major cause of morbidity and mortality for patients with SSc is respiratory failure due to pulmonary fibrosis. Despite how commonly interstitial lung disease (ILD) occurs in SSc, it remains poorly understood and represents a major unmet medical need. The Wnt/-catenin (-cat) signaling pathway is known to be crucial for cell fate decisions throughout development and adult tissue repair after injury. Work from our group and others have shown that the Wnt/β-cat pathway is aberrantly activated in systemic sclerosis and the associated ILD. Subsequent studies from our laboratory provided the first evidence that global genetic loss of the Wnt co-receptor Lrp5, resulting in reduced β-cat signaling, was protective against bleomycin-induced pulmonary fibrosis and that, in the peripheral blood mononuclear cells from two independent cohorts of Idiopathic Pulmonary Fibrosis (IPF) subjects, Wnt signaling as one of the top 2 over- represented pathways associated with worsened prognosis. We have generated extensive preliminary data demonstrating that sustained β-cat signaling in lung macrophages promotes the persistence of lung fibrosis after both bleomycin- and asbestos-induced injuries in mice, suggesting that macrophages are a key cell type through which -cat signaling drives fibrosis. Our preliminary data also reveal that the alveolar macrophage population is increased in SSc-ILD lungs, where lung transcriptomes from SSc-ILD and IPF subjects share common genes. Thus, based on these findings, we reason that the signals that drive macrophage recruitment, differentiation and perdurance after tissue injury are conserved across fibrotic diseases through a common Wnt/-cat regulatory axis. We hypothesize that Wnt/-cat signaling is required for the differentiation of monocytes into recruited alveolar macrophages and that injured lung alveolar epithelium provides a contextual Wnt signal that maintains a pro-fibrotic milieu for these recruited macrophages, thus aggravating lung repair and promoting the persistence of fibrosis. We propose 1) to determine the role Wnt/β-cat signaling to the differentiation of monocytes-macrophages in the persistence of fibrosis in SSc-ILD, 2) to determine the contribution of Wnt signaling from the injured alveolar epithelium in maintaining the pro-fibrotic macrophage phenotype in SSc-ILD, and 3) to determine the monocyte- macrophage subpopulations from subjects with SSc-ILD that express enrichment for Wnt pathway genes. We will use human blood and lung samples from subjects with SSc-ILD and complementary in vivo approaches using competitive and shielded chimeric mice, macrophage-specific transgenic mice targeting β-cat and Wnt ligands, and chemical ablation to dissect the relative contributions of Wnt/β-cat signaling in macrophages and epithelial cells necessary for repair after lung injury and in SSc-ILD where immune pathways are implicated.

项目摘要系统性硬化症（SSc）是一种进行性纤维化疾病，目前尚无有效的治疗方法。目前，SSc患者发病和死亡的主要原因是呼吸衰竭，肺纤维化尽管间质性肺疾病（ILD）在SSc中的发生率很高，这是一个未被满足的医疗需求。Wnt/β-catenin（β-cat）信号通路是一种已知在整个发育过程中对细胞命运决定和损伤后的成人组织修复至关重要。工作我们和其他人的研究表明，Wnt/β-cat通路在全身性疾病中被异常激活，硬化和相关ILD。我们实验室的后续研究提供了第一个证据， Wnt共受体Lrp 5的整体遗传缺失导致β-cat信号传导减少，博莱霉素诱导的肺纤维化，在两个人的外周血单核细胞中，特发性肺纤维化（IPF）受试者的独立队列，Wnt信号传导是前2个超过代表与预后恶化相关的途径。我们已经收集了大量的初步数据表明肺巨噬细胞中持续的β-cat信号促进了肺纤维化的持续在博来霉素和石棉诱导的小鼠损伤后，表明巨噬细胞是一种关键细胞， β-cat信号传导驱动纤维化的类型。我们的初步数据还显示， SSc-ILD肺中的巨噬细胞群增加，其中来自SSc-ILD和IPF的肺转录组实验对象有共同的基因因此，基于这些发现，我们推断，组织损伤后巨噬细胞的募集、分化和持久性在纤维化中是保守的，疾病通过共同的Wnt/β-cat调节轴。我们假设Wnt/β-cat信号传导是必需的，对于单核细胞分化为募集的肺泡巨噬细胞和损伤的肺泡巨噬细胞，上皮细胞提供了一个上下文Wnt信号，维持了这些招募的促纤维化环境，巨噬细胞，从而加重肺修复并促进纤维化的持续。我们建议（1）确定Wnt/β-cat信号在单核细胞-巨噬细胞分化中的作用， 2）确定SSc-ILD中来自受损肺泡上皮的Wnt信号传导的贡献，维持SSc-ILD中的促纤维化巨噬细胞表型，和3）确定单核细胞-巨噬细胞表型。来自SSc-ILD受试者的表达Wnt途径基因富集的巨噬细胞亚群。我们将使用来自SSc-ILD受试者的人血液和肺样本，并在体内进行补充方法使用竞争性和屏蔽嵌合小鼠，巨噬细胞特异性转基因小鼠靶向 β-cat和Wnt配体，以及化学消融，以剖析Wnt/β-cat信号传导在细胞凋亡中的相对贡献。肺损伤后和SSc-ILD中，免疫球蛋白、巨噬细胞和上皮细胞是修复所必需的。路是有牵连的。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Force-dependent allostery of the α-catenin actin-binding domain controls adherens junction dynamics and functions.

α-catenin肌动蛋白结合结构域的力依赖性变构控制着粘附的连接动力学和功能。

DOI：
10.1038/s41467-018-07481-7
发表时间：
2018-11-30
期刊：
Nature communications
影响因子：
16.6
作者：
Ishiyama N;Sarpal R;Wood MN;Barrick SK;Nishikawa T;Hayashi H;Kobb AB;Flozak AS;Yemelyanov A;Fernandez-Gonzalez R;Yonemura S;Leckband DE;Gottardi CJ;Tepass U;Ikura M
通讯作者：
Ikura M

Idiopathic Pulmonary Fibrosis and Lung Cancer: Finding Similarities within Differences.

特发性肺纤维化和肺癌：在差异中寻找相似之处。