Mechanotransduction in corneal disorders

角膜疾病中的机械传导

基本信息

批准号：
10321901
负责人：
CHRISTOPHER John MURPHY
金额：
$ 37.8万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321901
关键词：
Affect Age Age-Years Animal Model Animals Apoptosis Biophysics Blindness Bullous Keratopathy Cell Density Cell Proliferation Cells Cellular Stress Response Chronic Clinical Complex Cornea Corneal Diseases Corneal Endothelium Cues Data Data Aggregation Descemet&apos s membrane Disease Endothelial Cells Epithelial Attachment Event Extracellular Matrix Fuchs&apos Endothelial Dystrophy Functional disorder Glaucoma Goals Health Human In Vitro Injury Keratoplasty Kidney Knock-out Knockout Mice Knowledge Literature Mechanics Membrane Mitochondria Modeling Morphology Mus Myofibroblast Norepinephrine Onset of illness Oxidation-Reduction Oxidative Stress Participant Pathogenesis Pathology Patients Play Porosity Protein Kinase Regenerative capacity Rho-associated kinase Role Signal Transduction Stress Testing Time Transcription Coactivator UV Radiation Exposure Ultraviolet Rays Up-Regulation Wild Type Mouse aged cell behavior cell injury cell motility cell regeneration corneal epithelium early onset efficacy testing in vivo kinase inhibitor knock-down mechanical properties mechanotransduction mouse model novel therapeutics premature protein kinase inhibitor response rho sensor sight restoration transport inhibitor

项目摘要

PROJECT SUMMARY We have determined that transcriptional co-activators and mechanotransducers, YAP/TAZ, influence corneal epithelial contact guidance, myofibroblast transformation, and that TAZ (encoded by WWTR1 in humans and Wwtr1 in mice) is crucial for a healthy corneal endothelium. Corneal disease is a leading cause of blindness worldwide; corneal transplantation is often required to restore vision particularly for the common condition, Fuchs endothelial corneal dystrophy (FECD). Hallmarks of FECD include premature corneal endothelial cell (CEC) degeneration and the formation of excrescences of extracellular matrix (ECM), termed guttae, on Descemet’s membrane (DM). Biophysical cues intrinsic to ECMs are widely recognized as ubiquitous and potent modulators of myriad cell behaviors, including their response to stress. Despite this, there remains a major knowledge gap in regard to the mechanical properties of DM in health and disease and the associated mechanotransduction events in CECs. Furthermore, a large body of evidence points to oxidative stress playing a major role in FECD. Together, we hypothesize that TAZ plays a critical role in the onset and progression of FECD via changes in cell signaling, matrix remodeling, and cellular stress responses. Exciting preliminary data document that TAZ knockout (Wwtr1-/-) mice have reduced CEC density, increased cellular polymegathism, and an abnormal DM with guttae in comparison to wildtype (WT) littermates. Furthermore, CEC injury to TAZ deficient mice results in bullous keratopathy and diminished CEC regeneration similar to what is observed in severe, chronic FECD. These data suggest that TAZ deficient mice may represent an important late-onset model for FECD to define the role of mechanotransduction in its etiopathogenesis and to test new therapies to delay disease onset and/or progression. In this proposal, we utilize this model to test the efficacy of netarsudil, a rho-kinase and norepinephrine transport inhibitor, recently approved for glaucoma in the US. Preliminary data suggests that netarsudil increases CEC regeneration in TAZ deficient mice. The literature supports the use of rho-kinase inhibitors in CEC regeneration but netarsudil has never been studied in this context to our knowledge. The central goals of this proposal are to 1) determine the role of TAZ in CEC regeneration and 2) investigate the efficacy of netarsudil for CEC regeneration using murine models more predictive of human FECD.

项目概要我们已经确定转录共激活因子和机械传导因子 YAP/TAZ 会影响角膜上皮接触引导、肌成纤维细胞转化和 TAZ（在人类和动物中由 WWTR1 编码） Wwtr1（小鼠体内的 Wwtr1）对于健康的角膜内皮至关重要。角膜疾病是导致失明的主要原因。在世界范围内，通常需要角膜移植来恢复视力，特别是对于常见病症，Fuchs 内皮性角膜营养不良 (FECD) FECD 的标志包括角膜内皮细胞早熟 (CEC)。后弹力层上细胞外基质 (ECM) 的变性和赘生物（称为牙菌斑）的形成 ECM 固有的生物物理线索被广泛认为是普遍存在的有效调节剂。尽管如此，仍然存在重大的知识差距。关于 DM 在健康和疾病中的机械特性以及相关的机械传导此外，大量证据表明氧化应激在 FECD 中发挥着重要作用。我们共同探讨 TAZ 通过细胞变化在 FECD 的发生和进展中发挥关键作用信号传导、基质重塑和细胞应激反应令人兴奋的初步数据证明了 TAZ。敲除 (Wwtr1-/-) 小鼠的 CEC 密度降低、细胞多态性增加、DM 异常与野生型（WT）同窝小鼠相比，TAZ 缺陷小鼠的 CEC 损伤导致。大疱性角膜病变和 CEC 再生减少与严重慢性 FECD 中观察到的情况相似。这些数据表明，TAZ 缺陷小鼠可能代表 FECD 定义的重要迟发型模型。机械转导在其发病机制中的作用并测试新疗法以延迟疾病发作和/或在本提案中，我们利用该模型来测试 netarsudil（一种 rho 激酶）和去甲肾上腺素转运抑制剂最近在美国被批准用于治疗青光眼。 netarsudil 可增加 TAZ 缺陷小鼠的 CEC 再生文献支持使用 rho 激酶。 CEC 再生抑制剂，但据我们所知，奈塔舒地尔从未在这方面进行过研究。该提案的目标是 1) 确定 TAZ 在 CEC 再生中的作用，2) 研究 TAZ 的功效使用鼠模型进行 CEC 再生的 netarsudil 更能预测人类 FECD。