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，目前尚无治愈方法，患者会经历 在2-5分钟内逐渐丧失肺功能和导致呼吸衰竭的衰弱的肺部症状 在确诊数年后。IPF的特点是肺损伤和炎症，细胞外过度沉积 基质蛋白、成纤维细胞增生和瘢痕形成。患病率与年龄和 IPF是一种破坏性疾病，在老龄化过程中是一个严重的全球健康问题 世界人口。摩尔实验室的初步数据表明，肝素结合的表皮生长因子样蛋白 生长因子(HB-EGF)在纤维化的发生发展中可能起着至关重要的作用。HB-EGF是 在血管生成和伤口愈合中起重要作用的表皮生长因子受体(EGFR)配体，角质形成细胞 迁移和上皮-间充质转化。最近的临床研究表明，IPF患者的表达水平 HB-EGF及其受体高于确定的阈值更有可能经历疾病进展 (HR=8.772，P=0.0053，95%CI为1.905~40.385；HR=2.22，P=0.0251，95%CI为1.104~4.378)。 此外，HB-EGF作为预防纤维化进展的关键靶点的功能已被注意到 通过受体酪氨酸激酶(RTK)-EGFR特异性拮抗在动物模型中的成功。然而，临床上 对某些患者应用选择性RTK-EGFR抑制剂的试验可能会导致毒性和致命性，因此 有必要在纤维化的发展过程中更好地理解这一途径，以便能够更有针对性地 治疗选择。我们的实验室最近进行了一项初步研究，表明缺乏髓系特异性的小鼠 与野生型对照相比，HB-EGF可预防博莱霉素诱导的肺纤维化。这些数据 提示抑制髓系来源的HB-EGF可作为IPF患者的一种可行的治疗方法。 未来。这一建议将检验髓系细胞产生HB-EGF诱导肺泡形成的假设 促进肺纤维化发展的上皮细胞或成纤维细胞的改变。这 假说将通过三个具体目标进行检验：(1)证明髓系特异性HB-EGF的影响 关于小鼠肺纤维化的参数，(2)确定是否与可溶性或细胞相关的HB-EGF有关 对于上皮细胞或成纤维细胞的促纤维化改变，以及(3)确定HB-EGF是否主要通过 EGFR或HER4。为了实现这些特定的目标，小鼠细胞系和转基因小鼠模型 将用于进行适当的体外和体内实验，以研究细胞信号和细胞-细胞 有无髓系来源的HB-EGF的相互作用。这些创新研究的结果将确立 髓系HB-EGF信号对相关AEC和成纤维细胞激活结局的影响 未来的目标是确定髓系来源的HB-EGF作为患者的治疗靶点。该项目还将服务于 作为申请人获得研究和批判性思维核心技能的极好培训工具，以帮助她 成为一名成功的独立科学家。