Fibrillin-1 and TGFB2 Abnormality Models POAG Pathogenesis and Treatment

Fibrillin-1 和 TGFB2 异常模型 POAG 发病机制和治疗

基本信息

批准号：
9565409
负责人：
CHEE HIAN TAN
金额：
$ 38.83万
依托单位：
DOHENY EYE INSTITUTE
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 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9565409
关键词：
Affect Age Anterior Aqueous Humor Binding Binding Proteins Biochemical Biological Markers Blindness Chronic Clinical Complex Cornea DNA Sequence Alteration Development Disease Disease Progression Epithelial Cells Etiology Extracellular Matrix Eye FBN1 Feeds Genotype Glaucoma Goals Homeostasis Human Learning Light Link Mediating Mesenchymal Methodology Microfibrils Modeling Mus Mutation Optic Nerve Organ Pathogenesis Pathogenicity Pathologic Patients Peptides Pharmaceutical Preparations Phenotype Physiologic Intraocular Pressure Physiological Population Pre-Clinical Model Primary Open Angle Glaucoma Process Recombinants Regulation Resistance Retinal Ganglion Cells Risk Factors Role Route Signal Transduction Skin Source System TGFB2 gene Testing Therapeutic Thick Thrombospondin 1 Time Tissue imaging Tissues Titrations Trabecular meshwork structure Transforming Growth Factor Beta 2 Transforming Growth Factor beta Transforming Growth Factors Vision Wild Type Mouse anterior chamber aqueous clinical risk cytokine expectation feeding glaucoma test improved in vitro testing in vivo inhibitor/antagonist innovation mouse model mutant novel novel strategies prevent reconstitution response retinal damage targeted treatment therapeutic target treatment strategy tsk mouse two-photon vector

项目摘要

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.

项目概要/摘要原发性开角型青光眼 (POAG) 是全球范围内不可逆性失明的主要原因。长期目标是通过发现和加深理解来开发更有效的临床疗法我们希望了解如何在一定程度上改变潜在的疾病机制。显着改变疾病的自然病程，保留视力，并对患者的生活产生积极影响。对于治疗 POAG 等慢性顽疾尤其重要。 POAG 的病因不明，但临床特征和危险因素已知：眼压 (IOP)、年龄增加、角膜厚度增加和视网膜神经节细胞损失，转化生长因子 2 (TGFβ2) 水平增加。房水中的含量升高，可以被认为是一个重要的疾病生物标志物，这可以影响。小梁网通过诱导纤维化调节生理房水流出和眼压的功能变化和过度收缩导致的眼压升高会损害视网膜神经节细胞、视神经和想象。目前降低眼压的青光眼治疗针对的是眼压调节的生理机制，而不是首先，我们不能确定导致眼压升高的根本病理机制。治疗针对这些病理机制主要是因为我们不知道主要的原因是什么问题是。我们发现，具有 fibrillin-1 基因突变的小鼠惊人地模仿了显着的临床和症状人类 POAG 的生化特征小鼠的遗传缺陷立即引发致病性。它提供了一个独特的机会来更好地理解和治疗这种神秘的纤维蛋白-1。和重要疾病。我们提出以下具体目标：(1) 表征水性 TGFβ2 升高的来源；(2) 评估 TGFβ2 在眼组织和房水中的激活途径；(3) 测试预防有害的策略；水性 TGFβ2 对小梁网和 IOP 的影响会损害视网膜神经节细胞。小鼠模型将使我们能够更好地了解 POAG 中房水 TGFβ2 升高的基础并测试改善疾病发展和进展的治疗策略。