Myocardin in the pathogenesis of pleural remodeling

心肌素在胸膜重塑发病机制中的作用

基本信息

批准号：
10432067
负责人：
Steven Idell
金额：
$ 47.56万
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：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10432067
关键词：
Address Appearance Asbestos Attenuated Bacterial Pneumonia Biochemical Bleomycin Carbon Black Collagen Cytoskeleton Data Deposition Development Down-Regulation Empyema Engineering Extracellular Matrix Extracellular Matrix Proteins Fibronectins Fibrosis Functional Imaging Histologic Human Imaging Techniques Injury Label Lead Lung Lung diseases Mediating Medical Mesenchymal Modeling Molecular Morbidity - disease rate Motor Mouse Strains Mus Myofibroblast Outcome Pathogenesis Patient-Focused Outcomes Pharmacotherapy Phenotype Pleura Pleural Pleural Empyema Pleural Mesothelial Cell Protein Isoforms Proteins Radiation exposure Reporting Role Severities Signal Transduction Smooth Muscle Actin Staining Method Smooth Muscle Myosins Streptococcus Streptococcus pneumoniae Surface Techniques Testing Transforming Growth Factors Transportation Trauma Up-Regulation Visceral pleura Work X-Ray Computed Tomography base calponin defined contribution fibrotic lung improved outcome in vivo loss of function mouse model myocardin new therapeutic target novel pulmonary function

项目摘要

Pleural injury often leads to extensive remodeling of the pleural surfaces, which in severe cases leads to pleural fibrosis (PF). PF can occur as a result of bacterial pneumonia, trauma, radiation exposure and asbestos-related pleural injury. When severe, PF can cause restrictive lung disease or fibrothorax. PF with lung restriction is often seen in medical practice but current treatment is unsatisfactory and effective pharmacotherapy is not available. PF is characterized by proliferation of alpha-smooth muscle actin (α-SMA) expressing myofibroblasts. These myofibroblasts contribute to the thickening of the pleura via increased extracellular matrix deposition. The expansion of myofibroblasts is largely due to mesenchymal transition (MT) of resident pleural mesothelial cells, termed MesoMT. Our preliminary data show that TGF-β induces myocardin expression and activity. Further, myocardin and its effector proteins, smooth muscle myosin, calponin, and KIF5A are upregulated in our mouse models of pleural injury. Conversely, myocardin down- regulation attenuates TGF-β mediated induction of MesoMT marker, α-SMA, secretion of collagen and fibronectin and pleural fibrosis. We also reported that KIF5A is upregulated in TGF-β induced PF and critical for collagen secretion. Based on these observations and strong preliminary data, we strongly infer that myocardin expression and activation substantively contribute to the progression of PF. In this project, we will test the central hypothesis that the activation and upregulation of myocardin and its effector proteins are critical determinants in the acquisition of the activated PMC phenotypes and the progression of PF. Our objective is to test this postulate using state of the art cellular, biochemical, molecular, physiologic and imaging techniques. Primary human (H) and mouse (M) PMCs will be used to define mechanisms by which MesoMT is regulated. Three murine models will be used to assess the role of myocardin and KIF5 signaling in PF: carbon black/bleomycin (CBB) induced PF, Streptococcus pneumoniae-induced empyema/PF and TGF-β induced PF. Our specific aims are: 1) To define the mechanism of myocardin-induced MesoMT of HPMCs, 2) to define the mechanism of KIF5 activation in MesoMT and ECM deposition by HPMCs and 3) to define the contribution of myocardin and related effector proteins to neo-matrix deposition in the progression of PF in vivo. We will use new murine models of fibrosing pleural injury, including mice with mesothelial labelling to enable fate-mapping analyses, molecular, biochemical and immunohistochemical techniques with which we have expertise and state of the art CT imaging and pulmonary function analyses to accomplish these aims. The mechanism(s) by which TGF-β and myocardin regulate MesoMT and PF are currently unclear, representing potentially important gaps in our understanding of the pathogenesis of pleural organization and our ability to identify new therapeutic targets. This proposal addresses each of these gaps and predictably will identify novel targets that could be developed to improve outcomes of patients with PF/fibrothorax.

胸膜损伤通常会导致胸膜表面的大量重塑，在严重的情况下，这会导致胸膜纤维化（PF）。 PF可能是由于细菌肺炎，创伤，辐射暴露和石棉相关的胸膜损伤。严重时，PF会引起限制性肺部疾病或纤维状疾病。 PF与在医学实践中经常看到肺部限制，但目前的治疗不令人满意和有效药物治疗不可用。 PF的特征是α-平滑肌肌动蛋白（α-SMA）的增殖表达肌纤维细胞。这些肌纤维细胞通过增加而导致胸膜增厚细胞外基质沉积。肌纤维细胞的膨胀很大程度上是由于间充质转变（MT）居民的胸膜间皮细胞，称为中瘤。我们的初步数据表明，TGF-β诱导心肌表达和活性。此外，心肌蛋白及其效应蛋白，平滑肌肌球蛋白，在我们的胸膜损伤的小鼠模型中，Calponin和KIF5A上调。相反，心肌蛋白向下 - 调节会减弱TGF-β介导的Mesomt标记，α-SMA，胶原蛋白和分泌的诱导纤连蛋白和胸膜纤维化。我们还报道了KIF5A在TGF-β诱导的PF中进行了更新和关键用于胶原蛋白分泌。基于这些观察结果和强大的初步数据，我们强烈推断心肌表达和激活实质上有助于PF的进展。在这个项目中，我们将检验中心假设，即心肌蛋白及其效应蛋白的激活和上调至关重要在获取激活的PMC表型和PF进展的过程中的决定因素。我们的目标是使用艺术细胞，生化，分子，生理和成像技术测试这一假设。原代人（H）和小鼠（M）PMC将用于定义调节中瘤的机制。三种鼠模型将用于评估肌心蛋白和KIF5信号在PF中的作用：碳黑色/博来霉素（CBB）诱导的PF，肺炎链球菌诱导的脓肿/PF和TGF-β诱导的PF。我们的具体目的是：1）定义肌无力诱导的HPMC的Mesomt的机制，2）定义 HPMC中的Mesomt和ECM沉积中的KIF5激活机理，3）定义的贡献在体内PF进展中，心肌蛋白和相关效应蛋白与新矩阵沉积。我们将使用纤维胸膜损伤的新鼠模型，包括带有间皮标记的小鼠以实现命运映射分析，分子，生化和免疫组织化学技术，我们具有专业知识和最先进的CT成像和肺功能分析以实现这些目标。机制目前尚不清楚哪种TGF-β和心肌调节Mesomt和PF，代表了潜在的重要我们对胸膜组织发病机理的理解及其识别新疗法的能力的差距目标。该提议解决了这些差距，并且可以预见将确定可能是开发以改善PF/Fibrothorax患者的预后。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mitochondria-associated myosin 19 processively transports mitochondria on actin tracks in living cells.

DOI：
10.1016/j.jbc.2022.101883
发表时间：
2022-05
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Sato, Osamu;Sakai, Tsuyoshi;Choo, Young-yeon;Ikebe, Reiko;Watanabe, Tomonobu M.;Ikebe, Mitsuo
通讯作者：
Ikebe, Mitsuo

Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF Fibroblasts.

Caveolin-1 衍生肽可降低 IPF 成纤维细胞的 ER 应激并增强其明胶分解活性。