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.

项目摘要全身性硬化症（SSC）是一种进行性纤维化疾病，没有有效的治疗方法。目前，SSC患者的发病率和死亡率的主要原因是由于肺纤维化。尽管在SSC中通常发生间质肺疾病（ILD），但仍然很差理解并代表了主要的未满足医疗需求。 Wnt/-catenin（-cat）信号通路为已知对于整个发育过程中的细胞脂肪决策至关重要，受伤后成人组织修复。工作来自我们的小组和其他人表明，Wnt/β-cat途径在全身性中被异常激活硬化和相关的ILD。我们实验室的随后研究提供了第一个证据 Wnt共受体LRP5的全局遗传丧失，导致β-CAT信号降低，受到保护博来霉素诱导的肺纤维化，并在两个来自两个的外周血单核细胞中特发性肺纤维化（IPF）受试者的独立人群，Wnt信号传导是前2个过度的人之一代表与被遗忘的预后相关的途径。我们已经生成了广泛的初步数据证明肺巨噬细胞中持续的β-cat信号传导促进了肺纤维化的持久性在博来霉素和石棉诱导的小鼠损伤之后，这表明巨噬细胞是关键细胞 -cat信号传导驱动纤维化。我们的初步数据还表明肺泡巨噬细胞种群增加了SSC-ILD肺，其中SSC-ILD和IPF的肺转录组受试者共享共同基因。根据这些发现，我们认为驱动的信号巨噬细胞募集，组织损伤后的分化和per虫在纤维化范围内保存通过常见的Wnt/-CAT调节轴疾病。我们假设需要Wnt/-cat信号传导为了区分单核细胞为招募的肺泡巨噬细胞，肺肺泡受伤上皮提供了上下文Wnt信号，该信号维持这些招募的纤维环境巨噬细胞，从而加剧肺修复并促进纤维化的持续性。我们建议1）确定Wnt/β-CAT信号传导与单核细胞巨噬细胞分化的作用 SSC-ILD中的纤维化，2）确定受伤的肺泡上皮的Wnt信号的贡献维持SSC-ILD中的促纤维性巨噬细胞表型，并确定单核细胞来自具有SSC-ILD受试者的巨噬细胞亚群，这些受试者表达对Wnt途径基因的富集。我们将使用来自SSC-ILD和互补体内受试者的人类血液和肺样本使用竞争性和屏蔽的嵌合小鼠，巨噬细胞特异性转基因小鼠的方法 β-cat和Wnt配体，以及化学消融，以剖析Wnt/β-cat信号的相对贡献肺损伤后和在SSC-ILD中进行修复所需的巨噬细胞和上皮细胞。途径牵涉。

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）

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。

DOI：
10.1165/rcmb.2019-0172ed
发表时间：
2019
期刊：
American journal of respiratory cell and molecular biology
影响因子：
6.4
作者：
Reyfman,PaulA;Gottardi,CaraJ
通讯作者：
Gottardi,CaraJ

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

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