IGF-II regulates lung fibrosis in scleroderma

IGF-II 调节硬皮病肺纤维化

• 批准号: 10620791
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620791
• 关键词: Adult; Affect; Alleles; Binding; Binding Proteins; Biological; Biological Process; Cause of Death; Cell Differentiation process; 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; IGF1R gene; 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; 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; Prothrombin; Pulmonary Fibrosis; Receptor Protein-Tyrosine Kinases; Regulation; Rheumatism; Role; SOX9 protein; Scaffolding Protein; Scleroderma; Skin; Somatomedins; Stimulation of Cell Proliferation; Structure of parenchyma of lung; System; Systemic Scleroderma; Testing; Therapeutic; Transcript; Transcriptional Activation; Transforming Growth Factor beta; Tyrosine Kinase Receptor Inhibition; epigenetic regulation; human disease; human tissue; in vivo; insight; insulin regulation; novel; overexpression; prototype; 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

项目成果

Systemic sclerosis biomarkers detection in the secretome of TGFβ1-activated primary human lung fibroblasts.

TGFβ1 激活的原代人肺成纤维细胞分泌组中系统性硬化症生物标志物的检测。

• DOI: 10.1016/j.jprot.2021.104243
• 发表时间: 2021-06-30
• 期刊: Journal of proteomics
• 影响因子: 3.3
• 作者: Kendall RT;Renaud L;Baatz JE;Malaab M;Nguyen XX;Feghali-Bostwick CA
• 通讯作者: Feghali-Bostwick CA

The Role of SOX9 in IGF-II-Mediated Pulmonary Fibrosis.

• DOI: 10.3390/ijms241411234
• 发表时间: 2023-07-08
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

E4 engages uPAR and enolase-1 and activates urokinase to exert antifibrotic effects.

• DOI: 10.1172/jci.insight.144935
• 发表时间: 2021-12-22
• 期刊: JCI insight
• 影响因子: 8
• 作者: Sharma S;Watanabe T;Nishimoto T;Takihara T;Mlakar L;Nguyen XX;Sanderson M;Su Y;Chambers RA;Feghali-Bostwick C
• 通讯作者: Feghali-Bostwick C

Identification of Impacted Pathways and Transcriptomic Markers as Potential Mediators of Pulmonary Fibrosis in Transgenic Mice Expressing Human IGFBP5.

• DOI: 10.3390/ijms222212609
• 发表时间: 2021-11-22
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Nguyen XX;Renaud L;Feghali-Bostwick C
• 通讯作者: Feghali-Bostwick C

Phenotypic Characterization of Transgenic Mice Expressing Human IGFBP-5.

• DOI: 10.3390/ijms22010335
• 发表时间: 2020-12-30
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Nguyen XX;Sanderson M;Helke K;Feghali-Bostwick C
• 通讯作者: Feghali-Bostwick C