Pathogenic Wnt-beta catenin target genes in macrophages and fibrosis

巨噬细胞和纤维化中的致病性 Wnt-β 连环蛋白靶基因

基本信息

批准号：
9500544
负责人：
MONIQUE Evangeline HINCHCLIFF
金额：
$ 70.3万
依托单位：
YALE UNIVERSITY
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：
2019-07-03 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9500544
关键词：
Age Aging Alveolar Macrophages Animal Model Animals Attenuated Bioinformatics Biological Biology Biopsy Bleomycin Cell Separation Cells Cessation of life Characteristics Clinical Complex Connective Tissue Diseases Data Defect Dermal Development Disease Effector Cell Environment Esophagus Fibrosis Flow Cytometry Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Models Genetic Transcription Homeostasis Human Injury Irrigation Lead Link Longevity Lung Lung diseases Measures Molecular Multiple Sclerosis Mus Nature Organ Overlapping Genes Pathogenicity Pathway interactions Patients Phenotype Play Population Predisposition Process Pulmonary Fibrosis Pulmonology Reporting Resolution Resources Rheumatology Role Scleroderma Severities Severity of illness Signal Pathway Signal Transduction Skin System Systemic Scleroderma Technical Expertise Testing Tissue Differentiation Tissues Transforming Growth Factor beta Transplantation Universities Work age related aged beta catenin experimental study gain of function indium-bleomycin injured loss of function loss of function mutation lung development macrophage monocyte mouse model multidisciplinary next generation sequencing novel therapeutics prevent programs recruit skin disorder subcutaneous therapeutic target transcriptome transcriptome sequencing

项目摘要

Systemic sclerosis (SSc)/scleroderma, is the prototypic fibrotic disease causing skin and internal organ fibrosis. Lung fibrosis progression as a patient ages is the leading cause of SSc-related deaths. It is likely that a common effector cell drives fibrosis in multiple organs in SSc, and our preliminary data demonstrate that circulating monocytes are recruited to injured tissues where they differentiate into “monocyte-derived” macrophages. Using a murine model of lung fibrosis, we performed causal genetic experiments and showed that these monocyte-derived tissue macrophages are critical for the fibrosis development. Unbiased transcriptional profiling of flow-sorted monocyte-derived alveolar macrophages in mice during lung fibrosis, and in human alveolar macrophages from lung explants from patients with SSc undergoing transplantation, showed altered signaling through the Wnt/β-catenin pathway. We found that genetic loss-of- function in Wnt/β-catenin signaling in murine lung macrophages did not affect fibrosis severity, but sped the resolution of fibrosis. These findings are reminiscent of those in aged animals in which fibrosis persists much longer after bleomycin administration compared with young mice. Indeed, the persistence of fibrosis after injury is a characteristic feature of human fibrosis in multiple organs. Furthermore, we found age-related changes in Wnt/β-catenin pathway components in transcriptomes generated from flow sorted alveolar macrophages collected over the lifespan of mice (4-24 months). These findings support our hypothesis that a gain of function in Wnt/β-catenin signaling in monocyte-derived macrophages contributes to the age-related susceptibility to persistent fibrosis in multiple organs. We propose to test this hypothesis in two interrelated specific aims. In Aim 1, we will determine whether genetic gain- or loss-of-function of Wnt/β-catenin signaling in monocyte-derived macrophages cells enhances or prevents the differential susceptibility of aged animals to multiple organ fibrosis. In Aim 2, we will determine whether a common deregulated Wnt pathway-related gene expression signature is present in tissue macrophages isolated from the lung and skin of patients with SSc compared to healthy control subjects. Our previous work using whole skin biopsies from mice and SSc patients, demonstrated that alterations in the Wnt/β-catenin system are involved with SSc dermal fibrosis. We now propose to capitalize upon our combined expertise in macrophage biology and Wnt/β-catenin signaling to determine their contribution to accelerated SSc dermal and lung fibrosis in the aged. Altogether, this proposal matches a proven investigative team with a compelling hypothesis that stands to transform the way we think about aging-related fibrosis.

全身性硬化症（SSC）/硬皮病是原型纤维化疾病，导致皮肤和内部器官纤维化。肺纤维化的发展是患者年龄的主要原因。很可能一个常见的效应细胞驱动SSC多个器官的纤维化，我们的初步数据表明循环单核细胞被招募到受伤的组织中，在这些组织中，它们分化为“单核细胞衍生” 巨噬细胞。使用肺纤维化的鼠模型，我们进行了因果遗传实验，并显示了这些单核细胞衍生的组织巨噬细胞对于纤维化发育至关重要。公正肺纤维化过程中小鼠流动单核细胞衍生的肺泡巨噬细胞的转录分析和在接受移植的SSC患者的肺外植体的人肺泡巨噬细胞中通过Wnt/β-catenin途径改变了信号传导。我们发现Wnt/β-catenin中的遗传丧失功能鼠肺巨噬细胞中的信号传导不会影响纤维化的严重程度，而是刺激了纤维化的分辨率。这些发现让人联想到那些在博霉素后纤维化持续更长更长的年龄动物中的发现与小鼠相比，给药。实际上，受伤后纤维化的持久性是一个特征人体纤维化在多个器官中的特征。此外，我们发现Wnt/β-catenin与年龄相关的变化由流动分类的肺泡巨噬细胞产生的转录组中的途径成分，收集在小鼠的寿命（4-24个月）。这些发现支持我们的假设，即Wnt/β-catenin中功能的增长单核细胞衍生的巨噬细胞中的信号传导有助于与年龄相关的持续纤维化敏感性多个器官。我们建议在两个相互关联的特定目标中检验这一假设。在AIM 1中，我们将确定单核细胞衍生的Wnt/β-catenin信号的遗传获益或功能丧失巨噬细胞增强或防止年龄动物对多器官的差异敏感性纤维化。在AIM 2中，我们将确定常见的失调Wnt途径相关的基因表达是否与SSC患者的肺和皮肤分离的组织巨噬细胞中存在签名健康的控制受试者。我们以前使用来自小鼠和SSC患者的全皮肤活检的工作，证明Wnt/β-catenin系统的改变与SSC真皮纤维化有关。我们现在提出利用我们在巨噬细胞生物学和Wnt/β-catenin信号传导方面的联合专业知识的提议确定它们对年龄加速SSC皮肤和肺纤维化的贡献。总共，这项建议匹配一个经过验证的调查团队，并具有令人信服的假设，该假设代表着我们的思维方式关于与衰老有关的纤维化。