Fibrillin-1 and TGFB2 Abnormality Models POAG Pathogenesis and Treatment

项目概要/摘要 原发性开角型青光眼（primary open angle glaucoma，POAG）是世界范围内不可逆性失明的主要原因。此项目的 长期目标是通过发现和提高认识来开发更有效的临床治疗方法 青光眼的发病机制。我们想知道如何改变潜在的疾病机制， 显著改变疾病的自然进程，保护视力，并对患者的生活产生积极影响。这是 在治疗慢性顽固性疾病如原发性开角型青光眼时尤为重要。 POAG的病因不明，尽管临床特征和风险因素是已知的：眼内压（IOP）， 增加年龄、角膜厚度和视网膜神经节细胞损失。转化生长因子-2（TGF β 2）水平 在房水中的浓度升高，可以被认为是一种重要的疾病生物标志物。这可能会影响 小梁网通过诱导纤维化调节生理性房水流出量和眼压 变化和过度收缩。所导致的IOP升高损害视网膜神经节细胞、视神经和视神经， 视野 目前的降IOP青光眼治疗针对的是IOP调节的生理机制，而不是 首先是导致IOP升高的潜在病理机制。我们不能 治疗靶向这些病理机制，主要是因为我们不知道什么是主要的 问题是 我们已经发现，一只带有Escherin-1基因突变的小鼠， 人POAG的生化特征。老鼠的基因缺陷会立即引发致病性 与Escherin-1相关的机制。它提供了一个独特的机会，以更好地了解和对待这个神秘的 重要的疾病。 我们提出以下具体目标：（1）表征升高的水性TGF β 2的来源;（2）评估 TGF β 2在眼组织和房水中的活化途径;以及（3）测试预防有害的 TGF β 2水溶液对小梁网和损伤视网膜神经节细胞的IOP的影响。的 小鼠模型将使我们能够更好地理解POAG中水相TGF β 2升高的基础， 治疗策略，以改善疾病的发展和进展。

PROJECT SUMMARY/ABSTRACT Primary open angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide. This project's long-term goal is to develop more effective clinical therapy through the discovery and improved understanding of glaucoma pathogenesis. We want to learn how to modify underlying disease mechanisms to an extent that it significantly alters the natural course of disease, preserves vision, and positively impacts patients' lives. This is particularly important in dealing with a chronic, unrelenting disease such as POAG. POAG is of unknown cause, although clinical features and risk factors are known: intraocular pressure (IOP), increasing age, corneal thickness and retinal ganglion cell loss. Levels of transforming growth factor-2 (TGFβ2) in the aqueous humor are elevated and can be considered an important disease biomarker. This can affect the trabecular meshwork's function of regulating physiological aqueous outflow and IOP by inducing fibrogenic change and excessive contractility. Resulting rising IOP damages the retinal ganglion cells, optic nerve and vision. Current IOP-lowering glaucoma therapy targets physiological mechanisms of IOP regulation rather than underlying pathological mechanisms responsible for causing IOP to rise in the first place. We cannot therapeutically target these pathological mechanisms mainly because we do not know what the primary problem is. We have discovered that a mouse with a fibrillin-1 genetic mutation uncannily mimics salient clinical and biochemical features of human POAG. The genetic defect of the mouse immediately invokes pathogenic mechanisms related to fibrillin-1. It offers a unique opportunity to better understand and treat this mysterious and important disease. We propose the following specific aims to: (1) characterize the source of elevated aqueous TGFβ2; (2) assess routes of TGFβ2 activation in the eye tissues and aqueous humor; and (3) test a strategy to prevent harmful effects of aqueous TGFβ2 on the trabecular meshwork and IOP that damages retinal ganglion cells. The mouse model will allow us to better understand the basis for aqueous TGFβ2 elevation in POAG and test a treatment strategy to ameliorate development and progression of the disease.