Determining the Role of Myeloid-derived HB-EGF in Pulmonary Fibrosis

确定髓源性 HB-EGF 在肺纤维化中的作用

• 批准号: 10023169
• 负责人: Elissa Mairen Hult
• 金额: $ 3.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023169
• 关键词: Age; Aging; Alveolar; Animal Model; Animals; Apoptosis; Area; Attention; Biological; Bleomycin; CRISPR/Cas technology; Cell Communication; Cell Culture Techniques; Cell Maintenance; Cells; Cellular Structures; Cicatrix; Clinical; Clinical Data; Clinical Research; Clinical Trials; Coculture Techniques; Critical Thinking; Cultured Cells; DTR gene; Data; Deposition; Development; Diagnosis; Disease; Disease Progression; Environment; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Epithelium; ErbB4 gene; Erlotinib; Extracellular Matrix Proteins; Fibroblasts; Fibronectins; Fibrosis; Flow Cytometry; Functional Residual Capacity; Future; Gefitinib; Genetically Engineered Mouse; Growth Factor; Growth Factor Receptors; Heparin Binding; Hyperplasia; Impairment; In Vitro; Induced Mutation; Inflammation; Inflammatory; Injury; Kidney; Ligands; Link; Liver; Lung; Lung Compliance; Lung Inflammation; Lung diseases; Macrophage Activation; Measures; Mediating; Mediator of activation protein; Membrane; Mesenchymal; Methods; Mitosis; Modeling; Molecular; Mouse Cell Line; Mus; Myelogenous; Myeloid Cells; Myofibroblast; Outcome; Oxygen; Pathogenesis; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Physiology; Plasma; Population; Prevalence; Prevention; Production; Proteins; Pulmonary Fibrosis; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Regulation; Research; Respiratory Failure; Respiratory Signs and Symptoms; Respiratory physiology; Role; Scientist; Signal Transduction; Small Interfering RNA; Smooth Muscle Actin Staining Method; Source; Stomach; Surface; Testing; Therapeutic; Time; Toxic effect; Training; Tyrosine Kinase Inhibitor; alveolar epithelium; angiogenesis; animal data; collagenase; cytokine; experience; experimental study; global health; idiopathic pulmonary fibrosis; improved; in vivo; indium-bleomycin; inhibitor/antagonist; innovation; insight; keratinocyte; lung development; lung injury; macrophage; member; migration; monocyte; mortality; novel; pressure; receptor; recruit; skills; success; targeted treatment; therapeutic target; wound healing

Project Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no known cure, with patients experiencing a gradual loss of lung function and debilitating pulmonary symptoms that result in respiratory failure within 2-5 years after diagnosis. IPF is characterized by lung injury and inflammation, excessive deposition of extracellular matrix proteins, fibroblast hyperplasia, and scar formation. With prevalence highly associated with age and suboptimal treatment options, IPF is a devastating disease that is a serious global health concern in an aging world population. Preliminary data in the Moore lab suggest that heparin-binding epidermal growth factor-like growth factor (HB-EGF) may be critically important in the development and progression of fibrosis. HB-EGF is an EGF receptor (EGFR) ligand that has essential roles in angiogenesis and wound healing, keratinocyte migration and epithelial-mesenchymal transition. Recent clinical studies show that IPF patients expressing levels of HB-EGF and its receptor above an identified threshold are more likely to experience disease progression (HR=8.772, P=0.0053, 95% CI 1.905-40.385 and HR=2.2, P=0.0251, 95% CI 1.104-4.378 respectively). Furthermore, the functionality of HB-EGF as a key target in prevention of fibrosis progression has been noted via the success of receptor tyrosine kinase (RTK)-EGFR-specific antagonism in animal models. However, clinical trials administering select RTK-EGFR inhibitors can result in toxicity and lethality in some patients, and thus there is a need to better understand this pathway in the development of fibrosis to allow for more targeted therapeutic options. Our lab recently conducted a preliminary study showing that mice lacking myeloid-specific HB-EGF are protected from bleomycin-induced pulmonary fibrosis compared to wild type controls. These data suggest that inhibition of myeloid-derived HB-EGF could serve as a viable therapeutic for IPF patients in the future. This proposal will test the hypothesis that HB-EGF production from myeloid cells induces alveolar epithelial cell (AEC) or fibroblast alterations that promote the development of lung fibrosis. This hypothesis will be tested through three specific aims: (1) Demonstrate the impact of myeloid-specific HB-EGF on parameters of pulmonary fibrosis in mice, (2) Determine if soluble or cell-associated HB-EGF is responsible for profibrotic changes to epithelial cells or fibroblasts, and (3) Determine if HB-EGF primarily signals through EGFR or HER4. To accomplish these specific aims, mouse cell lines and genetically engineered mouse models will be used to perform the appropriate in vitro and in vivo experiments to study cell signaling and cell-cell interactions with and without myeloid-derived HB-EGF. The results from these innovative studies will establish the impacts of myeloid-HB-EGF signaling on relevant AEC and fibroblast activation outcomes with the overall future aim of identifying myeloid-derived HB-EGF as a therapeutic target for patients. This project will also serve as an excellent training vehicle for the applicant to gain core skills in research and critical thinking to help her become a successful and independent scientist.

项目摘要 特发性肺纤维化（IPF）是一种致命的肺部疾病，没有已知的治愈方法，患者患有A 肺功能的逐渐丧失和使肺部症状衰弱的肺部症状，导致2-5之内的呼吸衰竭 诊断后的几年。 IPF的特征是肺损伤和炎症，细胞外的过多沉积 基质蛋白，成纤维细胞增生和疤痕形成。与年龄高度相关的患病率和 次优治疗方案，IPF是一种毁灭性的疾病，在衰老中是严重的全球健康问题 世界人口。摩尔实验室中的初步数据表明肝素结合表皮生长因子样 生长因子（HB-EGF）在纤维化的发展和发展中至关重要。 HB-EGF是 EGF受体（EGFR）配体在血管生成和伤口愈合中具有重要作用，角质形成细胞 迁移和上皮间质转变。最近的临床研究表明，IPF患者表达水平 HB-EGF及其受体高于确定阈值的受体更有可能体验疾病进展 （HR = 8.772，P = 0.0053，95％CI 1.905-40.385和HR = 2.2，P = 0.0251，95％CI 1.104-4.378）。 此外，已经注意到HB-EGF作为预防纤维化进展的关键目标 通过动物模型中受体酪氨酸激酶（RTK）-EGFR特异性拮抗作用的成功。但是，临床 管理某些RTK-EGFR抑制剂的试验可能导致某些患者的毒性和致死性，因此 有必要更好地了解纤维化发展的这一途径，以实现更多针对性的 治疗选择。我们的实验室最近进行了一项初步研究，表明缺乏髓样特异性的小鼠 与野生型对照相比，HB-EGF免受博来霉素诱导的肺纤维化的保护。这些数据 建议抑制髓样衍生的HB-EGF可以作为IPF患者的可行治疗 未来。该提案将检验以下假设：髓样细胞产生HB-EGF会诱导肺泡 促进肺纤维化发展的上皮细胞（AEC）或成纤维细胞改变。这 假设将通过三个特定目的进行检验：（1）证明髓样特异性HB-EGF的影响 关于小鼠肺纤维化的参数，（2）确定可溶性或与细胞相关的HB-EGF是否负责 对于上皮细胞或成纤维细胞的纤维化变化，（3）确定HB-EGF是否主要通过 EGFR或HER4。为了实现这些特定目的，小鼠细胞系和基因工程的鼠标模型 将用于执行适当的体外和体内实验，以研究细胞信号和细胞细胞 有或没有髓样衍生的HB-EGF的相互作用。这些创新研究的结果将建立 髓样HB-EGF信号对相关AEC和成纤维细胞激活结果的影响与总体 将髓样衍生的HB-EGF鉴定为患者的治疗靶点的未来目标。这个项目也将服务 作为申请人获得研究和批判性思维核心技能以帮助她的出色训练工具 成为一名成功的独立科学家。