Fibrillin-1 and TGFB2 Abnormality Models POAG Pathogenesis and Treatment

项目摘要/摘要 原发性开角型青光眼(POAG)是世界范围内导致不可逆性失明的主要原因。这个项目的 长期目标是通过发现和提高理解来开发更有效的临床治疗方法 青光眼的发病机制。我们想要学习如何修改潜在的疾病机制，以使其 显著改变自然病程，保护视力，并对患者的生活产生积极影响。这是 在处理像POAG这样的慢性、顽固性疾病时尤其重要。 POAG的原因不明，尽管临床特征和危险因素已知：眼压(IOP)， 年龄增加，角膜厚度增加，视网膜神经节细胞丢失。转化生长因子-2(β-2)水平 在房水中升高，可被认为是一个重要的疾病生物标志物。这可能会影响 小梁网诱导纤维化调节生理性房水流出和眼压的作用 变化和过度收缩。由此导致的眼压升高损害了视网膜神经节细胞、视神经和 幻象。 目前的青光眼降眼压治疗针对的是眼压调节的生理机制，而不是 首先导致眼压升高的潜在病理机制。我们不能 针对这些病理机制进行治疗主要是因为我们不知道 问题是。 我们已经发现，带有纤维蛋白-1基因突变的小鼠不可思议地模仿了显著的临床和 人类开角型青光眼的生化特征。小鼠的遗传缺陷立即引发了致病 与纤维蛋白-1相关的机制。它提供了一个独特的机会来更好地理解和对待这个神秘的 也是重要的疾病。 我们提出以下具体目标：(1)确定房水转化生长因子β-2升高的来源；(2)评估 转化生长因子β2在眼组织和房水中的激活途径；以及(3)测试防止有害的策略 转化生长因子β-2房水对视网膜神经节细胞损伤的小梁网和眼压的影响这个 小鼠模型将使我们能够更好地了解POAG中房水转化生长因子β2升高的基础，并测试 改善疾病发展和进展的治疗策略。

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.