Dedicator of cytokinesis 2 in pleural fibrosis

胸膜纤维化中胞质分裂2的奉献者

基本信息

批准号：
10683791
负责人：
Guoqing Qian
金额：
$ 36.28万
依托单位：
UNIVERSITY OF TEXAS HLTH CTR AT TYLER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10683791
关键词：
Adipose tissue Asbestos Bleomycin Blood Coagulation Factor Blood Vessels Carbon Black Cells Cerebral Decortication Chest Cicatrix Clinical Collagen Cytokinesis Cytoskeletal Modeling Data Development Diet Disease Disease Progression Dyspnea Empyema Epithelial Event F-Actin Fatty acid glycerol esters Fibronectins Fibrosis Fructose Functional disorder Gene Expression Genes Goals Guanine Nucleotide Exchange Factors Hematopoietic Human Impairment Infection Inflammatory Intervention Knock-out Knockout Mice Knowledge Lead Lung diseases Manuscripts Mediating Mediator of activation protein Mesenchymal Mesothelial Cell Metabolic Modeling Molecular Morphology Mus Operative Surgical Procedures Outcome Pathogenesis Pathologic Processes Pathway interactions Patients Pharmacological Treatment Pharmacotherapy Phosphorylation Physiological Play Pleura Pleural Pleural Diseases Pleural Mesothelial Cell Pleurisy Pneumonia Process Public Health Pulmonary Inflammation Refractory Research Role Signal Pathway Signal Transduction Smooth Muscle Actin Staining Method Smooth Muscle Myocytes Snails Streptococcus pneumoniae Testing Therapeutic Intervention Thrombin Transforming Growth Factor beta Transforming Growth Factors Tuberculosis Up-Regulation base calretinin cell motility cell type clinically significant cytokine effusion epithelial to mesenchymal transition glycogen synthase kinase 3 beta in vivo injury and repair irradiation knock-down migration new therapeutic target novel novel therapeutics prevent pulmonary function repaired slug systemic inflammatory response targeted treatment transcription factor

项目摘要

Pleural fibrosis is the scarring of the pleura resulting in restrictive lung disease and impaired lung function. The pathophysiological mechanism of pleural fibrosis is unclear. The interactions between resident and inflammatory cells, profibrotic mediators and coagulation factors, and fibrinolytic pathways are integral to pleural remodeling and fibrosis. Increasing evidence affirm the critical role of pleural mesothelial cells (PMCs) in pleural fibrosis development, mainly through a process termed mesothelial to mesenchymal transition (MesoMT). MesoMT is characterized by increased expression of α-smooth muscle actin (α-SMA)/collagen 1 (Col-1)/fibronectin (FN), and enhanced cell migration/invasion. Currently, there are no pharmacologic treatments for this disease. Therefore, identification of novel targets and therapeutic strategies is an important goal for the public health. However, there is a fundamental knowledge gap in mechanisms controlling MesoMT during pleural fibrosis. Our preliminary data strongly support that dedicator of cytokinesis 2 (DOCK2) is a crucial regulator of MesoMT to promote pleural fibrosis. In primary human PMCs (HPMCs), DOCK2 was induced by the potent MesoMT inducer TGF-β. DOCK2 knockdown blocked TGFβ-induced MesoMT maker expression and cell migration. Snail as a transcriptional factor controlling epithelial to mesenchymal transition was found critical in TGF-β-induced MesoMT. DOCK2 knockdown inhibited TGF-β-induced Snail expression and activation of Smad2/3 and NF-κB signaling, which have been shown to upregulate Snail expression in various cell types. In addition, we found that DOCK2 was dramatically induced in the fibrotic pleura of human pleuritis patients and in pleural fibrosis models induced by Streptococcus pneumoniae (Strep), carbon black/bleomycin (CBB), and TGF-β. DOCK2 knockout mice were significantly protected from Strep-induced pleural fibrosis. Based on these findings, our overall hypothesis is that DOCK2 mediates MesoMT and increases PMC migration/invasion to promote pleural fibrosis, which will be tested in three specific aims. In Aim 1, we will determine if DOCK2 promotes pleural MesoMT via upregulation of Snail. Further, we will test whether DOCK2 increases Snail through activating Smad2/3 and NF-κB signaling. In Aim 2, we will test if DOCK2 promote pleural MesoMT with increased cell migration/invasion. Specifically, we will determine if DOCK2 mediates TGF-β-induced cytoskeletal reorganization, migration/invasion via activating Rac1. In Aim 3, we will test the hypothesis that DOCK2 knockout blocks pleural fibrosis via inhibiting MesoMT in vivo. We will determine if general and mesothelial cell-specific DOCK2 knockout mice are protected from Strep, CBB, and TGF-β induced pleural fibrosis through suppressing MesoMT in vivo. Completion of the proposed studies will establish the pivotal role and mechanisms of DOCK2 in promoting pleural fibrosis by regulating MesoMT, which may ultimately contribute to the identification of novel targeted therapies for this important but refractory clinical problem.