Epidermal Growth Factor Receptor Signaling in Fibrotic Skin Disease

纤维化皮肤病中的表皮生长因子受体信号传导

• 批准号: 10653037
• 负责人: Ian D Odell
• 金额: $ 17.23万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653037
• 关键词: Affect; Autoimmune Diseases; Binding Proteins; Biological Models; Biological Process; Bleomycin; Blood Vessels; Bone Marrow; Cells; Cessation of life; Chimera organism; Chronic; Chronic Phase; Co-Immunoprecipitations; Collagen; Complex; Development; Diabetes Mellitus; Disease; Doxycycline; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epiregulin; Excision; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Fc Receptor; Fibroblasts; Fibrosis; Functional disorder; Future; Gefitinib; Gene Expression; Genes; Goals; Heart; Hematopoietic; Hereditary Disease; Histologic; Histology; Human; Immune; Immune system; Individual; Inflammatory; Interferon Receptor; Interferons; Investigation; Kidney; Knockout Mice; Knowledge; Lead; Ligands; Liver; Lung; Maintenance; Mass Spectrum Analysis; Measures; Mesenchymal; Modeling; Modification; Morbidity - disease rate; Mus; Obesity; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Pericytes; Phase; Phenotype; Phosphorylation; Post-Translational Protein Processing; Process; Production; Proteins; Proteomics; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; STAT1 gene; Scleroderma; Signal Pathway; Signal Transduction; Skin; Stem cell transplant; System; Techniques; Testing; Time; Tissues; Wild Type Mouse; Work; cell type; chronic graft versus host disease; chronic inflammatory disease; conditional knockout; effective therapy; graft vs host disease; improved; in vivo; inducible gene expression; insight; mortality; mouse model; new therapeutic target; novel; promoter; response; skin disorder; skin fibrosis; skin organogenesis; small molecule inhibitor; transcription factor; virtual

PROJECT SUMMARY/ABSTRACT Fibrosis is a common final outcome of most human chronic inflammatory diseases and has been estimated to contribute to almost half of all deaths in the world 1. It can result from autoimmune diseases such as scleroderma, after stem cell transplant in graft-vs-host disease, from chronic inflammatory conditions associated with obesity and diabetes and through inherited genetic disorders. Fibrosis can affect virtually any organ including the skin, lungs, kidneys, liver, heart and blood vessels. Scleroderma and graft-vs-host disease most commonly affect the skin and the degree of skin involvement is associated with higher mortality and internal organ dysfunction 2,3, suggesting common underlying mechanisms. We previously identified in these diseases activation of epidermal growth factor receptor (EGFR) on fibroblasts by its immune cell derived ligand epiregulin. This proposal aims to further elucidate the major gaps in our knowledge of how EGFR signaling drives fibrosis in the skin. In particular, it is unclear what signaling pathways downstream of EGFR activation are critical to different phases of fibrosis and how these targets cross-talk with other fibrosis-associated pathways. In this project, we examine the cellular signals that result from chronic EGFR activation in fibroblasts and pericytes and their cross-talk with STAT1, an essential transcription factor for regulating interferon-dependent gene expression. In our first aim, we will characterize the effects of EGFR activation in fibroblasts and pericytes using a Tet-On expression system. This model system will allow temporal and cell-type control of EGFR activation in vivo. We will analyze what EGFR pathways are activated and required for development of skin fibrosis, and their effects on the immune system. In the second aim, we will examine the relevant cell types in which STAT1 signaling is required for development of fibrosis using bone marrow chimeras and STAT1 conditional knockout mice. We will investigate whether EGFR and STAT1 signaling are co-dependent and utilize proteomics techniques to discover protein interactions and modifications. Together, these aims will provide better insight into the pathogenesis of fibrotic skin disease, lead to a broader understanding of fibrosis as a biological process, and help develop new treatments that may substantially impact patients' lives.

项目总结/摘要 纤维化是大多数人类慢性炎性疾病的常见最终结果，并且据估计， 造成了世界上几乎一半的死亡1。它可以由自身免疫性疾病如硬皮病引起， 移植物抗宿主病中干细胞移植后，与肥胖相关的慢性炎症性疾病 和糖尿病以及遗传性遗传疾病。纤维化可以影响几乎任何器官，包括皮肤， 肺、肾脏、肝脏、心脏和血管。硬皮病和移植物抗宿主病最常影响 皮肤和皮肤受累程度与较高的死亡率和内脏功能障碍相关2，3， 暗示了共同的潜在机制。我们以前在这些疾病中发现了表皮细胞的激活， 生长因子受体（EGFR）通过其免疫细胞衍生配体表皮调节蛋白（epiregulin）作用于成纤维细胞。这项建议旨在 进一步阐明了我们对EGFR信号传导如何驱动皮肤纤维化的认识中的主要空白。特别是， 目前还不清楚EGFR激活的下游信号通路对纤维化的不同阶段至关重要， 以及这些靶点如何与其他纤维化相关途径相互作用。 在这个项目中，我们研究了成纤维细胞中慢性EGFR激活引起的细胞信号， 周细胞及其与STAT 1的相互作用，STAT 1是调节干扰素依赖性 基因表达。在我们的第一个目标中，我们将描述成纤维细胞和周细胞中EGFR激活的作用。 使用Tet-On表达系统。该模型系统将允许EGFR的时间和细胞类型控制 体内激活。我们将分析哪些EGFR途径被激活以及皮肤发育所需 纤维化及其对免疫系统的影响。在第二个目标中，我们将研究相关的细胞类型， 其中STAT 1信号传导是使用骨髓嵌合体和STAT 1 条件性基因敲除小鼠我们将研究EGFR和STAT 1信号转导是否是共依赖的， 蛋白质组学技术，发现蛋白质的相互作用和修改。总之，这些目标将提供更好的 深入了解纤维化皮肤病的发病机制，从而更广泛地了解纤维化作为一种生物学 这一过程，并帮助开发新的治疗方法，可能会大大影响病人的生活。

项目成果

IL-6 trans-signaling in a humanized mouse model of scleroderma.

• DOI: 10.1073/pnas.2306965120
• 发表时间: 2023-09-12
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Odell, Ian D.;Agrawal, Kriti;Sefik, Esen;Odell, Anahi V.;Caves, Elizabeth;Kirkiles-Smith, Nancy C.;Horsley, Valerie;Hinchcliff, Monique;Pober, Jordan S.;Kluger, Yuval;Flavell, Richard A.
• 通讯作者: Flavell, Richard A.

Epiregulin is a dendritic cell-derived EGFR ligand that maintains skin and lung fibrosis.

• DOI: 10.1126/sciimmunol.abq6691
• 发表时间: 2022-12-16
• 期刊: Science immunology
• 影响因子: 24.8