IGF-II regulates lung fibrosis in scleroderma

IGF-II 调节硬皮病肺纤维化

• 批准号: 10027971
• 负责人: Carol A. Feghali-Bostwick
• 金额: $ 37.38万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10027971
• 关键词: Adult; Affect; Alleles; Binding; Binding Proteins; Biological; Biological Process; Cause of Death; Cell Differentiation process; Cell Proliferation; Cell Surface Receptors; Characteristics; Chromosome 11; Clinical; Collagen; Connective Tissue Diseases; DNA Methylation; Data; Disease; Endothelium; Equilibrium; Etiology; Extracellular Matrix; Fetal Development; Fibroblasts; Fibronectins; Fibrosis; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; H19 gene; Homeostasis; Human; Hybrids; IGFBP1 gene; Immediate-Early Genes; In Vitro; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like Growth Factor Receptor; Knowledge; Laboratories; Liver; Lung; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Messenger RNA; Methylation; Morbidity - disease rate; Mus; Organ; Organ Culture Techniques; Organ Transplantation; Organ failure; Pathogenesis; Patients; Peptides; Phenotype; Phosphorylation; Platelet-Derived Growth Factor; Production; Protein Isoforms; Pulmonary Fibrosis; Receptor Activation; Receptor Protein-Tyrosine Kinases; Regulation; Rheumatism; Role; SOX9 protein; Scaffolding Protein; Scleroderma; Skin; Somatomedins; Structure of parenchyma of lung; System; Systemic Scleroderma; Testing; Therapeutic; Transcript; Transforming Growth Factor beta; Tyrosine Kinase Receptor Inhibition; epigenetic regulation; human disease; human tissue; in vivo; insight; insulin regulation; novel; overexpression; receptor; response; therapy development; transcription factor

ABSTRACT Organ fibrosis is an irreversible endpoint of several diseases, leading to organ failure. Systemic sclerosis (SSc) is a prototypic multisystem fibrotic disease with fibrosis affecting multiple organs including the lung. SSc has the highest case fatality among rheumatic diseases and lung involvement is currently the leading cause of death of patients with this disease. The only available therapeutic option for patients with fibrosis is organ transplantation, which is clinically impossible on the scale necessary. The hallmark of fibrosis in multiple organs is the disruption of extracellular matrix (ECM) homeostasis, resulting in accumulation of ECM components and subsequent organ failure. We identified IGF-II as a gene overexpressed in SSc lung tissues, whereas in the adult IGF-II is only expressed in the liver. The role of IGF-II in pulmonary fibrosis and in SSc remains unexplored. We show that IGF-II promotes fibrosis in vitro in primary pulmonary fibroblasts, in vivo in mouse lungs, and ex vivo in human tissue in organ culture. We also show that IGF-II promotes its effects via increasing expression of ECM components, tipping the MMP:TIMP balance in favor of a fibrotic milieu, and inducing expression of TGFb isoforms, thus recapitulating the fibrotic phenotype. We hypothesize that IGF-II promotes fibrosis via engagement of hybrid IGF-IR/IR receptors, activation of the transcription factors Egr-1 and Sox9 and subsequent phosphorylation of the scaffold protein NEDD9. We also propose that increased expression of IGF-II in SSc lung is due to epigenetic regulation. We propose to test our hypothesis with the following specific aims: 1) Define the factors that promote the IGF-II-mediated fibrotic phenotype. Specifically we will determine the role of the transcription factors Sox-9 and Egr-1 in orchestrating the effects of IGF-II and the role of the scaffold protein NEDD9 in mediating the response to IGF-II; 2) Identify the receptors mediating the effects of IGF-II on fibroblasts by blocking IGF-IR, IR, and IGF-IIR and inhibiting receptor tyrosine kinase activity; and 3) Examine the regulation of IGF-II gene expression in SSc by examining if IGF-II mRNA in SSc lung fibroblasts shows biallelic expression and assessing the methylation status of the IGF-II—H19 locus. Our findings will provide new insights into the pathogenesis of fibrosis in SSc and other fibrotic disorders and will result in the identification of new targets for the development of therapies. Our approach will result in findings that are of direct relevance to the human disease, will advance mechanistic knowledge of the response to IGF-II, and a rationale for targeting IGF-II and/or its receptor(s) as a therapeutic strategy in SSc.

摘要 器官纤维化是几种疾病的不可逆终点，导致器官衰竭。系统性硬化症（SSc） 是一种典型的多系统纤维化疾病，其纤维化影响包括肺在内的多个器官。南南合作 风湿性疾病中病死率最高，肺部受累是目前 患者死于这种疾病。纤维化患者唯一可用的治疗选择是器官移植。 移植，这在临床上是不可能的。多发性骨髓瘤纤维化的标志 器官的一个重要特征是细胞外基质（ECM）稳态的破坏，导致ECM的积累。 成分和随后的器官衰竭。我们确定IGF-II是SSc肺组织中过表达的基因， 而在成人中，IGF-II仅在肝脏中表达。IGF-II在肺纤维化和SSc中的作用 仍然未被探索。我们发现，IGF-II在体外促进原代肺成纤维细胞的纤维化，在体内促进肺成纤维细胞的纤维化，在体外促进肺成纤维细胞的纤维化，在体内促进肺成纤维细胞的纤维化。 小鼠肺，以及在器官培养中的离体人组织。我们还表明，IGF-II促进其作用，通过 增加ECM组分的表达，使MMP：TIMP平衡倾向于纤维化环境，以及 诱导TGF β同种型的表达，从而重现纤维化表型。我们假设IGF-II 通过与IGF-IR/IR杂合受体结合，激活转录因子， Egr-1和Sox 9以及随后的支架蛋白NEDD 9的磷酸化。我们亦建议 SSc肺中IGF-II表达的增加是由于表观遗传调节。我们建议测试我们的 1）定义促进IGF-II介导的纤维化的因素， 表型具体地说，我们将确定转录因子Sox-9和Egr-1在协调 IGF-II的作用和支架蛋白NEDD 9在介导对IGF-II的应答中的作用; 2）鉴定 受体通过阻断IGF-IR、IR和IGF-IIR并抑制IGF-II对成纤维细胞的作用， 受体酪氨酸激酶活性;和3）通过检测SSc中IGF-II基因表达来检测SSc中IGF-II基因表达的调节。 如果SSc肺成纤维细胞中的IGF-II mRNA显示双等位基因表达， IGF-II-H19基因座。我们的研究结果将为SSc和其他疾病的纤维化发病机制提供新的见解。 纤维化疾病，并将导致识别新的目标，用于发展的治疗。我们 这种方法将导致与人类疾病直接相关的发现， 了解对IGF-II的反应，以及靶向IGF-II和/或其受体作为治疗药物的基本原理 战略在SSc。