Role of MRTF signaling in proliferative vitreoretinopathy

MRTF 信号在增殖性玻璃体视网膜病变中的作用

• 批准号: 10440078
• 负责人: Shigeo Tamiya
• 金额: $ 25.68万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440078
• 关键词: Actins; Affect; Animal Model; Atomic Force Microscopy; Back; Blindness; Calcium; Cell Nucleus; Cells; Characteristics; Cicatrix; Collagen; Complication; Contracts; Cultured Cells; Data; Deposition; Development; Disease; Enzymes; Epiretinal Membrane; Extracellular Matrix; Eye Injuries; Family; Feedback; Feeds; Fibronectins; Fibrosis; Gene Expression; Goals; In Vitro; Intervention; Literature; Liver Fibrosis; Measures; Molecular; Muller' s cell; Myofibroblast; Myosin Light Chain Kinase; Nuclear; Nuclear Translocation; Operative Surgical Procedures; PTK2B gene; Patients; Phosphotransferases; Prevention; Production; Proliferative Vitreoretinopathy; Protein Inhibition; Protein-Lysine 6-Oxidase; Publishing; Pulmonary Fibrosis; Retina; Retinal Detachment; Role; Sampling; Series; Serum Response Factor; Signal Transduction; Small Interfering RNA; Structure of retinal pigment epithelium; Surface; Testing; Time; Tissues; Traction; Transforming Growth Factor beta; Transglutaminases; Vanilloid; Visual Acuity; base; cell type; crosslink; cytokine; fibrillogenesis; in vivo; knock-down; molecular targeted therapies; myocardin; polymerization; porcine model; prevent; receptor; repaired; rho; small hairpin RNA; src-Family Kinases; therapeutic target; transcription factor; transdifferentiation; wound

Project Summary/Abstract Proliferative vitreoretinopathy (PVR) is a fibrotic complication affecting the retina. In PVR, loss of visual acuity, and in severe cases blindness, is caused by contraction of scar tissue that form on the retinal surface. PVR is found in ~50% of posterior segment ocular trauma cases and about 5% of cases after surgical repair of rhegmatogenous retinal detachment. Reliable treatment for PVR is currently unavailable, and therefore, prevention is important. The overall goal of this project is to unravel molecular mechanisms involved in PVR development to identify targets for potential intervention. The trigger for fibrosis such as PVR is sustained presence of myofibroblasts, a cell type specialized ECM deposition and wound contraction. Recent studies show that stiff ECM activates intracellular signaling essential for differentiation of myofibroblasts. Myofibroblasts, in turn, feeds back to further enhances ECM stiffness via aberrant ECM deposition and crosslinking. This positive feedback loop between myofibroblasts and ECM rigidity sustains myofibroblast presence, and its inhibition successfully prevented lung and liver fibrosis in animal models. However, the underlying detailed mechanisms and molecules involved are both tissue and cell type dependent, and the role of this positive feedback loop is yet to be examine in PVR. Past studies show the presence of molecules involved in ECM stiffening in samples from PVR patients. Our preliminary data show two key molecules known to be affected by ECM stiffness, transient receptor potential vanilloid 4 (TRPV4) channel and myocardin-related transcription factor (MRTF), are required for myofibroblast transdifferentiation of retinal pigment epithelial (RPE) and Müller glia cells, two resident cell types that give rise to myofibroblasts in PVR. Further, data also show another molecule regulated by stiffness and known to alter MRTF target expression, TAZ, interacts with MRTF. We propose studies to determine molecular mechanisms activated by ECM stiffness leading to myofibroblast differentiation and PVR. In Aim1, the effect of ECM stiffening molecules on myofibroblast differentiation and PVR will be examine. Detailed molecular mechanism of regulating MRTF, which is key to myofibroblast differentiation, by TRPV4 and TAZ will be determined in Aim2 and 3, respectively. The project has the potential to uncover key molecular therapeutic targets for the prevention of PVR, and possibly other fibrotic diseases.

项目摘要/摘要 增殖的玻璃体肾上腺病（PVR）是影响视网膜的纤维化并发症。在PVR中，视觉丧失 敏锐度和在严重的情况下，是由视网膜上形成的疤痕组织收缩引起的 表面。 PVR在约50％的后段眼部创伤病例中发现，大约5％的病例 Rhegmatogentos视网膜脱离的手术修复。目前无法使用PVR的可靠治疗 因此，预防很重要。该项目的总体目标是解开分子机制 参与PVR开发以识别潜在干预的目标。纤维化的触发因素，例如 PVR是肌成纤维细胞的持续存在，一种细胞类型的ECM沉积和伤口 收缩。最近的研究表明，硬性ECM激活细胞内信号传导对于分化必不可少的 肌纤维细胞。肌纤维细胞反过来反馈以进一步增强ECM刚度通过异常ECM 沉积和交联。肌纤维细胞和ECM刚度之间的这种积极的反馈回路维持 肌纤维细胞的存在及其抑制作用成功地阻止了动物模型中的肺和肝纤维化。 但是，涉及的基本详细机制和分子既是组织和细胞类型 依赖性以及这种积极反馈循环的作用尚未在PVR中进行检查。过去的研究表明 PVR患者样品中涉及ECM僵硬的分子的存在。我们的初步数据显示 两个关键分子已知受ECM刚度影响，瞬态受体电势香草素4（TRPV4） 肌成纤维细胞需要通道和心肌相关转录因子（MRTF） 视网膜色素上皮（RPE）和müller胶质细胞的转差，两种居民细胞类型 在PVR中升至肌纤维细胞。此外，数据还显示了另一个由刚度调节的分子，已知 改变MRTF靶表达TAZ与MRTF相互作用。我们提出的研究以确定分子 ECM刚度激活的机制导致肌纤维细胞分化和PVR。在AIM1中，效果 将检查在肌纤维细胞分化和PVR上的ECM僵硬分子的僵硬分子。详细的分子 TRPV4和TAZ的调节MRTF的机制，这是肌纤维细胞分化的关键的机制 分别在AIM2和3中确定。该项目有可能发现关键分子疗法 预防PVR的靶标，甚至可能是其他纤维化疾病。