Therapeutic Inhibition of Optic Nerve Head Gliosis and Fibrosis in Glaucoma

青光眼视神经乳头胶质增生和纤维化的治疗抑制

基本信息

批准号：
10202607
负责人：
Gillian Jane McLellan
金额：
$ 35.01万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202607
关键词：
Address Adult Affect Angiotensin II Animal Model Animals Axon Blindness Blood Pressure Cell Culture Techniques Chronic Disease Cicatrix Clinical Trials Complement Data Development Diagnosis Disease Progression Drug Kinetics Electrophysiology (science)Extracellular Matrix Eye FDA approved Family Felidae Felis catus Fibrosis Functional disorder GTP-Binding Protein alpha Subunits, Gs Gene Expression Profiling Gene Proteins Genetic Models Glaucoma Gliosis Goals Human In Situ Life Ligands Measures Mediating Mediator of activation protein Modeling Neuroglia Onset of illness Operative Surgical Procedures Optic Disk Optic Nerve Oral Outcome PPAR gamma Pathogenesis Pathologic Pathway interactions Patients Perfusion Pharmaceutical Preparations Physiologic Intraocular Pressure Play Prevalence Property Proteins Randomized Receptor, Angiotensin, Type 1 Research Retinal Ganglion Cells Role Safety Signal Transduction Site Structure TGF Beta Signaling Pathway Techniques Testing Therapeutic Transcript Transforming Growth Factor beta Translations Treatment Efficacy Vision Visual axon injury clinical efficacy clinically relevant combinatorial differential expression expectation experience experimental study glial activation human tissue improved in vivo innovation insight molecular pathology nerve damage neuron loss new therapeutic target optic nerve disorder optic nerve regeneration preclinical study preclinical trial preservation pressure receptor targeted treatment telmisartan therapeutic target tool treatment effect treatment strategy

项目摘要

Project Summary: Optic nerve damage is a primary contributor to debilitating vision loss in glaucoma. The prevalence of glaucoma is increasing in the USA and worldwide and there is an urgent need for new, accessible treatments to improve visual outcomes in glaucoma patients. To date, lowering of intraocular pressure (IOP) remains the only treatment strategy with proven efficacy in preserving vision in glaucoma. However, IOP-lowering drugs and surgeries are not effective in all patients, and many patients with seemingly controlled IOP still experience progressive loss of vision. Transforming growth factor-beta (TGF-β) has emerged as playing a key role in progression of optic nerve damage, promoting glial cell activation, extracellular matrix remodeling and, ultimately, formation of glial scar in the optic nerve head (ONH). The overall goal of this application is to provide insight into the effects of blocking angiotensin II type1 receptor (AT1) on glaucoma progression. Our central hypothesis is that AT1 blockade will down-regulate TGF-β expression and pro-fibrotic pathways to ameliorate optic nerve axon loss and glial scarring in glaucoma. In Aim 1: To determine the clinical efficacy of AT1 blocker therapy on the progression of glaucomatous optic neuropathy in vivo, a pre-clinical study will be conducted in a spontaneous glaucoma model. To test the working hypothesis that AT1 blocker therapy will preserve axons and limit scarring in the optic nerve in glaucoma, functional (electrophysiological) and structural (OCT-derived) measures of glaucoma progression in vivo and axon counts in situ will be compared between eyes receiving IOP-lowering therapy alone and in combination with AT1 blocker and untreated eyes, in adult subjects with established glaucoma. In Aim 2: To determine if AT1-blockade affects pathways associated with gliosis and fibrosis in the ONH in this model, gene expression profiling will complement studies that focus on quantifying and localizing mediators of fibrosis in the TGF-β signaling pathway in ONHs in situ in treated subjects relative to untreated controls. These studies will utilize an existing, FDA-approved AT1 blocker with favorable pharmacokinetics, safety profile and unique properties likely to enhance its anti-fibrotic and neuro- protective effects. Significant innovation and strengths of this proposal include the lack of exogenous experimental manipulations to induce glaucoma in a unique, spontaneous model of glaucoma that recapitulates many important features of glaucoma in human patients. The research proposed will enhance mechanistic insight and provide proof of concept that treatment strategies that mitigate the effects of TGF-β signaling limit loss of visual function in spontaneous glaucoma, lending support to a new paradigm for the adjunctive therapy of glaucoma patients.

项目摘要：视神经损伤是使青光眼视力丧失使人衰弱的主要因素。流行率美国和全球的青光眼正在增加，迫切需要新的，可访问的治疗改善青光眼患者的视觉结局。迄今为止，降低眼内压（IOP）仍然是仅在维护青光眼的视力方面具有可证明有效性的治疗策略。但是，降低IOP的药物并且手术在所有患者中都不有效，许多看似控制IOP的患者仍然经历渐进的视力丧失。转化生长因子β（TGF-β）已出现，是在视神经损伤的进展，促进神经胶质细胞激活，细胞外基质重塑和最终，在视神经头（ONH）中形成神经胶质疤痕。该应用程序的总体目标是提供有关阻断血管紧张素II型受体（AT1）对青光眼进展的影响的洞察力。我们的中心假设是AT1封锁将下调TGF-β表达和促纤维化途径青光眼中的改善视神经轴突丧失和神经胶质疤痕。在AIM 1中：确定 AT1阻滞剂治疗在体内绿白糖性视神经病变进展，临床前研究将是在赞助青光眼模型中进行。为了检验工作假设，即AT1阻滞剂治疗将保存轴突并限制青光眼，功能（电生理）和结构的视神经中的疤痕（OCT衍生的）在体内和原位的体内和轴突计数的衡量标准之间将进行比较单独接受降低IOP疗法并与AT1阻滞剂和未处理的眼睛结合使用的眼睛，成人具有既定青光眼的受试者。在AIM 2中：确定AT1-Blockade是否影响与之相关的途径在该模型中，在ONH中的神经胶质和纤维化，基因表达分析将补充关注的研究量化和定位纤维化的纤维化介质在TGF-β信号传导途径中的原位治疗中的原位相对于未经处理的对照的受试者。这些研究将利用现有的，FDA批准的AT1阻止器有利的药代动力学，安全性和独特的特性，可能会增强其抗纤维化和神经性保护作用。该提案的重大创新和优势包括缺乏外源性实验性操纵以诱导独特的，赞助的青光眼模型，以诱导青光眼概括了人类患者青光眼的许多重要特征。提出的研究将增强机械洞察力并提供了减轻TGF-β影响的治疗策略的概念证明信号传递极限损失在赞助青光眼中的视觉功能，对新范式的贷款支持青光眼患者的辅助治疗。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Outer retinal thickness and visibility of the choriocapillaris in four distinct retinal regions imaged with spectral domain optical coherence tomography in dogs and cats.

DOI：
10.1111/vop.12989
发表时间：
2022-05
期刊：
VETERINARY OPHTHALMOLOGY
影响因子：
1.6
作者：
Mischi, Elisa;Soukup, Petr;Harman, Christine D.;Oikawa, Kazuya;Kowalska, Malwina E.;Hartnack, Sonja;McLellan, Gillian J.;Komaromy, Andras M.;Pot, Simon A.
通讯作者：
Pot, Simon A.

Mapping retinal ganglion cell somas in a large-eyed glaucoma model.

在大眼青光眼模型中绘制视网膜神经节细胞胞体。

DOI：
发表时间：
2021
期刊：
Molecular vision
影响因子：
2.2
作者：
Adelman,SaraA;Oikawa,Kazuya;Senthilkumar,Gopika;Trane,RalphMøller;Teixeira,LeandroBC;McLellan,GillianJ
通讯作者：
McLellan,GillianJ

Microstructure and resident cell-types of the feline optic nerve head resemble that of humans.

猫科动物视神经头的微观结构和常驻细胞类型与人类相似。