Trabecular Meshwork Cytoskeletal Signaling-Regulation of Aqueous Humor Outflow

小梁网细胞骨架信号传导-房水流出的调节

• 批准号: 8657438
• 负责人: P VASANTHA Rao
• 金额: $ 38.47万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657438
• 关键词: Acceleration; Accounting; Adhesives; Age; Agreement; Animal Model; Animals; Aqueous Humor; Architecture; Automobile Driving; Basement membrane; Biological Models; Blindness; Cells; Cicatrix; Clinical Trials; Collagen; Communities; Connective Tissue; Deposition; Development; Drainage procedure; Endothelin-1; Exhibits; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Eye; Fibroblasts; GTP Phosphohydrolase Activators; Generations; Glaucoma; Goals; Human; Intercellular Junctions; Knowledge; Life; Link; Lipids; Lysophospholipids; Mechanics; Mediating; Mesenchymal; Modeling; Molecular; Molecular Profiling; Myofibroblast; Ocular Hypertension; Open-Angle Glaucoma; Optics; Pathway interactions; Patients; Physiologic Intraocular Pressure; Physiological; Pirfenidone; Play; Primary Open Angle Glaucoma; Process; Production; Property; Proteins; Rattus; Regulation; Research; Resistance; Rho-associated kinase; Risk Factors; Role; Signal Pathway; Signal Transduction; Smooth Muscle Actin Staining Method; Specimen; Staging; Structure of sinus venosus of sclera; Testing; Tissues; Trabecular meshwork structure; Transforming Growth Factor Beta 2; United States; Work; base; cell type; connective tissue growth factor; effective therapy; human tissue; insight; kinase inhibitor; lysophosphatidic acid; myocardin; novel; novel strategies; novel therapeutics; public health relevance; response; rho; rho GTP-Binding Proteins; slug; transcription factor

DESCRIPTION (provided by applicant): Primary open-angle glaucoma (POAG) is the second leading cause of blindness in the United States and is commonly associated with elevation of intraocular pressure (IOP) resulting from increased resistance to aqueous humor (AH) outflow through the trabecular meshwork (TM) and Schlemm's canal (SC). Although IOP is considered to be a primary risk factor for open angle glaucoma, the etiological mechanisms responsible for increased resistance to AH outflow are largely unknown. The long-range goal of this application is to identify specific etiological mechanisms underlying increased resistance to AH outflow through the TM and SC, and leverage this knowledge to develop novel and targeted therapies for lowering IOP in glaucoma patients. We recently developed an animal model that exhibits a sustained increase in IOP in response to expression of a constitutively active Rho GTPase (RhoAV14) in the AH outflow pathway. Based on the highly significant and promising preliminary observations derived from this model, we propose a novel hypothesis that ocular hypertension induced by aberrant Rho/Rho kinase signaling activity in the trabecular outflow pathway is mechanistically linked to an enhanced endothelial to mesenchymal transition of TM and SC cells into matrix producing myofibroblast-like cells, the activation of which results in extracellular matrix (ECM) deposition and changes in juxtacanalicular connective tissue (JCT) architecture, leading to increased resistance to AH outflow. This central hypothesis is supported by our findings of scarring of the JCT, ECM accumulation and expression of myofibroblast-specific markers in the trabecular pathway of RhoAV14-induced ocular hypertensive rat eyes and in human POAG donor eyes. We propose to investigate this novel hypothesis under three specific aims: 1. Establish the role of Rho/Rho kinase signaling in driving the endothelial to mesenchymal transition (EndMT) of TM and SC cells into matrix-producing myofibroblast-like cells, upon exposure to mechanical strain and physiologically relevant factors (TGF-¿, autotaxin/LPA axis, connective tissue growth factor) associated with glaucoma; 2. Verify the mechanistic link between ocular hypertension in the RhoAV14 rat model, increased EndMT of TM and SC cells into myofibroblast-like cells, structural alterations within AH outflow pathway tissues, and increased resistance to AH outflow, and 3. Evaluate the validity of the prediction that the efficacy of Rho kinase inhibitors to increase AH outflow in ocular hypertensive glaucomatous eyes is linked partly to suppression of ECM deposition and fibrogenic effects of activated myofibroblasts in AH outflow pathway, using the RhoAV14 ocular hypertensive rat as a model system. Exploration of these studies is expected to identify the specific etiological mechanisms involved in increased resistance to AH outflow in glaucoma subjects and enhance our mechanistic understanding of how certain physiological factors and Rho kinase inhibitors influence AH outflow and IOP in glaucoma patients.

描述（由适用提供）：主要的开角青光眼（POAG）是美国失明的第二大主要原因，通常与通过小梁网络（TM）和Schlemm的Canal（SC）（SC）（sc）（sc）（AH）出口的耐药性（AH）出口增加而导致的眼内压（IOP）。尽管IOP被认为是开头青光眼的主要危险因素，但导致对AH出口耐药性增加的病因机制在很大程度上是未知的。该应用的远距离目标是通过TM和SC鉴定对AH出口抗性的特定病因机制，并利用这些知识来开发新型和有针对性的疗法，以降低青光眼患者的IOP。我们最近开发了一种动物模型，该模型表现出IOP持续增加，以响应AH出口途径中组成型活性Rho GTPase（RhoAV14）的表达。基于该模型得出的高度显着且有前途的初步观察，我们提出了一个新的假设，即小梁出口途径中异常的Rho/Rho激酶信号传导引起的眼部高血压在机械上与增强的内皮层与内皮的细胞中的细胞和SC细胞的细胞进行了序列化的细胞分类，从而将基质的细胞分类为细胞的细胞分类，从而在机械上与增强的内皮相关。矩阵（ECM）沉积和近距离结缔组织（JCT）结构的变化，导致对AH出口的耐药性增加。我们在RhoAV14诱导的眼睛高血压大鼠眼睛和人POAG供体眼中的JCT，ECM的积累和肌纤维细胞特异性标记物的疤痕，ECM积累和表达的结果得到了支持。我们建议在三个具体目的下研究这一新假设：1。建立Rho/Rho激酶信号传导在将TM和SC细胞的内皮层到内皮层次过渡（ENDMT）中的作用，从而使基质产生基质的肌纤维细胞类似于机械应力和物理相关因素（TGF-tgf-lap）（自动固定因子，自动固定因子，tgf--青光眼； 2。验证在Rhoav14大鼠模型中眼高血压之间的机理联系，增加了TM和SC细胞的末端末端到肌纤维细胞样细胞中，AH出口途径组织内的结构变化以及对AH出口的耐药性以及3。评估rho Kinase抑制作用的效率，以使Rho Kinuce抑制的效率增加，以使Rho Kinase抑制的效率增加。使用Rhoav14眼部高血压大鼠作为模型系统，激活的肌纤维细胞在AH出口途径中激活的肌纤维细胞的ECM沉积和纤维化作用。预计这些研究的探索将确定青光眼受试者对AH出口的耐药性增加的特定病因机制，并增强我们对某些生理因素和Rho激酶抑制剂如何影响青光眼患者AH出口和IOP的机械理解。