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.

项目概要：视神经损伤是导致青光眼视力丧失的主要原因。青光眼在美国和世界范围内不断增加，迫切需要新的、可行的治疗方法迄今为止，降低眼压（IOP）仍然是改善青光眼患者视力的方法。然而，降眼压药物是唯一被证明能有效保留青光眼视力的治疗策略。并且手术并非对所有患者都有效，许多眼压看似得到控制的患者仍然会出现转化生长因子-β (TGF-β) 已在视力逐渐丧失中发挥着关键作用。视神经损伤的进展，促进神经胶质细胞活化，细胞外基质重塑，最终，在视神经乳头（ONH）中形成神经胶质疤痕。该应用的总体目标是。深入了解阻断血管紧张素 II 1 型受体 (AT1) 对青光眼进展的影响。中心假设是 AT1 阻断将下调 TGF-β 表达和促纤维化途径改善青光眼中的视神经轴突损失和神经胶质疤痕目标 1：确定临床疗效。 AT1阻滞剂治疗青光眼视神经病变体内进展，临床前研究将进行在自发性青光眼模型中进行，以测试 AT1 阻滞剂治疗有效的假设。保护轴突并限制青光眼视神经、功能性（电生理学）和结构性疤痕（OCT 衍生的）青光眼体内进展测量和原位轴突计数将在接受单独降眼压治疗和联合 AT1 阻滞剂治疗的眼睛以及未经治疗的成人眼睛目标 2：确定 AT1 阻断是否影响与青光眼相关的通路。该模型中 ONH 中的神经胶质增生和纤维化，基因表达谱将补充关注的研究在治疗中原位量化和定位 ONH 中 TGF-β 信号通路中的纤维化介质这些研究将使用 FDA 批准的现有 AT1 阻断剂。良好的药代动力学、安全性和独特的特性可能会增强其抗纤维化和神经功能该提案的重大创新和优势包括缺乏外源性影响。在独特的自发青光眼模型中诱导青光眼的实验操作这项研究概括了人类患者青光眼的许多重要特征。机制洞察并提供减轻 TGF-β 影响的治疗策略的概念证明信号限制自发性青光眼的视觉功能丧失，为治疗新的范例提供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。