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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.

项目概要系统性硬化症（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 中常见，但其情况仍然很差理解并代表了一个重大的未满足的医疗需求。 Wnt/-连环蛋白 (-cat) 信号通路是已知对整个发育过程中的细胞命运决定和损伤后的成体组织修复至关重要。工作我们小组和其他人的研究表明，Wnt/β-cat 通路在全身系统中被异常激活。硬化症和相关的 ILD。我们实验室的后续研究提供了第一个证据： Wnt 辅助受体 Lrp5 的整体遗传缺失，导致 β-cat 信号传导减少，可以预防博来霉素诱导的肺纤维化，在来自两种的外周血单核细胞中在特发性肺纤维化 (IPF) 受试者的独立队列中，Wnt 信号传导是最重要的 2 个过度信号传导之一代表与预后恶化相关的途径。我们已经生成了大量的初步数据证明肺巨噬细胞中持续的 β-cat 信号传导促进肺纤维化的持续存在在博来霉素和石棉诱导小鼠损伤后，表明巨噬细胞是关键细胞 -cat 信号传导驱动纤维化的类型。我们的初步数据还表明，肺泡 SSc-ILD 肺部巨噬细胞数量增加，其中来自 SSc-ILD 和 IPF 的肺转录组受试者具有共同的基因。因此，根据这些发现，我们推断驱动信号组织损伤后巨噬细胞的募集、分化和持久性在纤维化过程中是保守的通过共同的 Wnt/-cat 调节轴来治疗疾病。我们假设需要 Wnt/-cat 信号传导用于将单核细胞分化为募集的肺泡巨噬细胞并损伤肺泡上皮细胞提供了一种背景性 Wnt 信号，为这些招募的细胞维持促纤维化环境巨噬细胞，从而加剧肺部修复并促进纤维化的持续存在。我们建议 1) 确定 Wnt/β-cat 信号传导对单核细胞-巨噬细胞分化在持久性中的作用 SSc-ILD 中的纤维化，2) 确定受损肺泡上皮中 Wnt 信号传导的贡献维持 SSc-ILD 中的促纤维化巨噬细胞表型，以及 3) 确定单核细胞来自 SSc-ILD 受试者的巨噬细胞亚群，表达 Wnt 通路基因的富集。我们将使用来自 SSc-ILD 受试者的人类血液和肺部样本，并在体内进行补充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的方法 β-cat 和 Wnt 配体，以及化学消融来剖析 Wnt/β-cat 信号传导的相对贡献肺损伤后和 SSc-ILD 中免疫修复所必需的巨噬细胞和上皮细胞路径受到牵连。

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。