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: 9885797
• 负责人: Shigeo Tamiya
• 金额: $ 39万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 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/9885797
• 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; Family; Family suidae; Feedback; Feeds; Fibronectins; Fibrosis; Gene Expression; Goals; In Vitro; Intervention; Literature; Liver Fibrosis; Measures; Modeling; 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; Trauma; Vanilloid; Visual Acuity; base; cell type; crosslink; cytokine; fibrillogenesis; in vivo; knock-down; molecular targeted therapies; myocardin; polymerization; 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 增生性玻璃体视网膜病变(PVR)是一种影响视网膜的纤维化并发症。在PVR中，视力丧失 视力，在严重的情况下失明，是由视网膜上形成的疤痕组织收缩引起的 浮出水面。约50%的后节眼外伤患者存在PVR，约5%的患者在术后发生PVR 孔源性视网膜脱离的手术修复目前还没有可靠的PVR治疗方法， 因此，预防很重要。这个项目的总体目标是解开分子机制。 参与PVR开发，以确定潜在干预的目标。引发纤维化的因素包括 PVR是持续存在的肌成纤维细胞，是一种细胞类型的特化ECM沉积和创伤 收缩。最近的研究表明，僵硬的ECM激活细胞内分化所必需的信号 肌成纤维细胞。反过来，肌成纤维细胞通过异常的细胞外基质反馈进一步增强细胞外基质的硬度。 沉积和交联剂。肌成纤维细胞和细胞外基质刚性之间的这种正反馈环路持续 肌成纤维细胞的存在及其抑制成功地预防了动物模型中的肺和肝纤维化。 然而，潜在的详细机制和涉及的分子是组织和细胞类型的 这种正反馈环的作用在PVR中还有待研究。过去的研究表明， PVR患者样本中存在参与细胞外基质硬化的分子。我们的初步数据显示 已知受细胞外基质刚性影响的两个关键分子--瞬时受体电位香草素4(TRPV4) 肌成纤维细胞需要通道和肌钙蛋白相关转录因子 视网膜色素上皮(RPE)和Müler胶质细胞的转分化，这两种常驻细胞类型 在PVR中上升为肌成纤维细胞。此外，数据还显示了另一种受刚性调节的分子，已知 ALTER MRTF目标表达TAZ与MRTF相互作用。我们建议进行研究以确定分子 细胞外基质僵硬激活导致肌成纤维细胞分化和PVR的机制。在Aim1中，效果 ECM硬化分子对肌成纤维细胞分化和PVR的影响将被研究。详细分子 TRPV4和TAZ调节肌成纤维细胞分化的关键因子MRTF的机制将是 分别在AIM2和3中确定。该项目有可能发现关键的分子治疗方法 预防PVR的目标，可能还有其他纤维性疾病。