Therapeutic Inhibition of Optic Nerve Head Gliosis and Fibrosis in Glaucoma

项目总结： 视神经损伤是导致青光眼视力下降的主要因素。疾病的流行 青光眼在美国和全世界都在增加，迫切需要新的、可获得的治疗方法 以改善青光眼患者的视力结果。迄今为止，降低眼压(IOP)仍然是 青光眼保存视力的唯一有效的治疗策略。然而，降眼压药物 而且手术并不是对所有患者都有效，许多眼压似乎得到控制的患者仍然体验到 进行性失明。转化生长因子-β(tgf-β)在血管紧张性疾病中起着关键作用。 视神经损伤的进展，促进胶质细胞激活，细胞外基质重塑， 最终，在视神经头(ONH)形成胶质瘢痕。此应用程序的总体目标是 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。我们的 中心假设是AT1阻断将下调转化生长因子-β的表达和促纤维化途径，从而 改善青光眼视神经轴突丢失和胶质瘢痕形成。目标1：确定阿司匹林的临床疗效 AT1阻滞剂治疗青光眼视神经病变的体内进展，将进行临床前研究 在自发性青光眼模型中进行。为了验证AT1受体阻滞剂治疗将 在功能性(电生理)和结构性青光眼中保留轴突和限制视神经瘢痕形成 (OCT得出的)体内青光眼进展的测量方法和原位轴突计数将在 接受单独和联合AT1阻滞剂和未治疗眼的成人降眼压治疗 确诊为青光眼的受试者。目标2：确定AT1-阻滞剂是否影响与 在ONH模型中，基因表达谱将补充以下研究 原位治疗ONH中转化生长因子-β信号通路中纤维化介质的定量和定位 受试者与未经处理的对照组相比。这些研究将使用FDA批准的现有AT1阻滞剂 良好的药代动力学、安全性和独特的性质可能增强其抗纤维化和神经保护作用。 起到保护作用。这一建议的重大创新和优势包括缺乏外源 在一种独特的自发性青光眼模型中诱导青光眼的实验操作 概括了人类青光眼患者的许多重要特征。拟议的研究将增强 机制洞察和提供概念证据，减轻转化生长因子-β影响的治疗策略 信号限制自发性青光眼视功能的丧失，为治疗自发性青光眼的新范式提供支持 青光眼患者的辅助治疗。

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.