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， 肺功能逐渐丧失和衰弱性肺部症状，导致2-5年内呼吸衰竭 诊断后几年。IPF的特征是肺损伤和炎症，细胞外基质过度沉积， 基质蛋白、成纤维细胞增生和瘢痕形成。患病率与年龄高度相关， 次优治疗选择，IPF是一种破坏性疾病，是老龄化人群中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， 生长因子（HB-EGF）可能在纤维化的发展和进展中至关重要。EGF是 表皮生长因子受体（EGFR）配体，在血管生成和伤口愈合、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患者表达水平 HB-EGF及其受体高于确定的阈值更可能经历疾病进展 (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，HB-EGF作为预防纤维化进展的关键靶点的功能已经被注意到 通过受体酪氨酸激酶（RTK）-EGFR特异性拮抗作用在动物模型中的成功。但临床 施用选择的RTK-EGFR抑制剂的试验可在一些患者中导致毒性和致死性， 需要更好地理解纤维化发展中的这一途径， 治疗选择我们的实验室最近进行了一项初步研究，表明缺乏骨髓特异性 与野生型对照相比，HB-EGF受到博来霉素诱导的肺纤维化的保护。这些数据 提示抑制骨髓来源HB-EGF可作为IPF患者的可行治疗方法， 未来该建议将验证骨髓细胞产生HB-EGF诱导肺泡上皮细胞增殖的假设。 上皮细胞（AEC）或成纤维细胞的改变，促进肺纤维化的发展。这 将通过三个具体目标来检验假设：（1）证明骨髓特异性HB-EGF的影响 （2）确定是否可溶性或细胞相关的HB-EGF负责 上皮细胞或成纤维细胞的促纤维化变化，和（3）确定HB-EGF是否主要通过 EGFR或HER 4。为了实现这些特定的目标，小鼠细胞系和基因工程小鼠模型 将用于进行适当的体外和体内实验，以研究细胞信号传导和细胞-细胞 与骨髓来源的HB-EGF的相互作用。这些创新研究的结果将建立 骨髓-HB-EGF信号传导对相关AEC和成纤维细胞活化结果的影响， 未来的目标是确定骨髓来源的HB-EGF作为患者的治疗靶点。该项目还将为 作为申请人获得研究和批判性思维核心技能的绝佳培训工具， 成为一名独立的科学家。