IGF-II regulates lung fibrosis in scleroderma

IGF-II 调节硬皮病肺纤维化

基本信息

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
项目类别：
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

项目摘要

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.

抽象的器官纤维化是多种疾病的不可逆转的终点，导致器官衰竭（SSc）。是一种典型的多系统纤维化疾病，纤维化影响包括肺在内的多个器官。风湿性疾病中病死率最高，肺部受累是目前导致该病的主要原因纤维化患者唯一可用的治疗选择是器官。移植，这在临床上不可能达到所需的规模，这是多发性纤维化的标志。器官的破坏是细胞外基质 (ECM) 稳态的破坏，导致 ECM 的积累我们确定 IGF-II 是 SSc 肺组织中过度表达的基因，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。我们的研究表明，IGF-II 在体外促进肺原代成纤维细胞的纤维化，在体内则促进肺原代成纤维细胞的纤维化。我们还表明，IGF-II 通过小鼠肺和离体器官培养中的人体组织来促进其作用。增加 ECM 成分的表达，使 MMP:TIMP 平衡向有利于纤维化环境的方向倾斜，以及诱导 TGFb 同种型的表达，从而重现纤维化表型。通过混合 IGF-IR/IR 受体的参与、转录因子的激活促进纤维化我们还提出 Egr-1 和 Sox9 以及随后的支架蛋白 NEDD9 的磷酸化。 SSc 肺中 IGF-II 表达增加是由于表观遗传调控。具有以下具体目标的假设： 1) 定义促进 IGF-II 介导的纤维化的因素具体来说，我们将确定转录因子 Sox-9 和 Egr-1 在协调中的作用。 2）鉴定IGF-II的作用以及支架蛋白NEDD9在介导IGF-II反应中的作用；通过阻断 IGF-IR、IR 和 IGF-IIR 并抑制 IGF-II 介导 IGF-II 对成纤维细胞作用的受体受体酪氨酸激酶活性；3) 通过检查来检查 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并评估 IGF-II 的甲基化状态 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，并将导致我们的疗法开发的新靶标的确定。该方法将产生与人类疾病直接相关的发现，将推进机制对 IGF-II 反应的了解，以及针对 IGF-II 和/或其受体作为治疗药物的基本原理 SSc 策略。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

E4 与 uPAR 和烯醇化酶-1 结合并激活尿激酶以发挥抗纤维化作用。

DOI：
发表时间：
2021-12-22
期刊：
影响因子：
8
作者：
Sharma, Shailza;Watanabe, Tomoya;Nishimoto, Tetsuya;Takihara, Takahisa;Mlakar, Logan;Nguyen, Xinh;Sanderson, Matthew;Su, Yunyun;Chambers, Roger A;Feghali
通讯作者：
Feghali

Role of Extracellular Vesicles in the Propagation of Lung Fibrosis in Systemic Sclerosis.

细胞外囊泡在系统性硬化症肺纤维化传播中的作用。

DOI：
发表时间：
2023-12
期刊：
影响因子：
0
作者：
Mouawad, Joe E;Sanderson, Matthew;Sharma, Shailza;Helke, Kristi L;Pilewski, Joseph M;Nadig, Satish N;Feghali
通讯作者：
Feghali

Phenotypic Characterization of Transgenic Mice Expressing Human IGFBP-5.

表达人 IGFBP-5 的转基因小鼠的表型特征。

DOI：
发表时间：
2020-12-30
期刊：
影响因子：
5.6
作者：
Nguyen, Xinh;Sanderson, Matthew;Helke, Kristi;Feghali
通讯作者：
Feghali

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

SOX9 在 IGF-II 介导的肺纤维化中的作用。

DOI：
发表时间：
2023-07-08
期刊：
影响因子：
5.6
作者：
Waldrep, Kristy M;Rodgers, Jessalyn I;Garrett, Sara M;Wolf, Bethany J;Feghali
通讯作者：
Feghali

Pulmonary fibrosis: something old, something new…still waiting for a breakthrough.

肺纤维化：旧的、新的……仍在等待突破。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Feghali
通讯作者：
Feghali

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Carol A. Feghali-Bostwick其他文献

Transcriptional regulation of increased CCL2 expression in pulmonary fibrosis involves nuclear factor-κB and activator protein-1

肺纤维化中 CCL2 表达增加的转录调节涉及核因子

DOI：
发表时间：
2013
期刊：
International Journal of Biochemistry & Cell Biology
影响因子：
0
作者：
Linhua Pang;Mingyan Xu;Chao Yuan;Liqin Yin;Xihe Chen;Xiaoqiong Zhou;Guanwu Li;Yucai Fu;Carol A. Feghali-Bostwick
通讯作者：
Carol A. Feghali-Bostwick