Unfolded Protein Response in Glaucoma Pathogenesis

青光眼发病机制中未折叠的蛋白质反应

• 批准号: 8370742
• 负责人: MARKUS H. KUEHN
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370742
• 关键词: Address; Adolescent; Adult; Affect; American; Animal Model; Aqueous Humor; Blindness; Cell Death; Cells; Chronic; Clinical; Clinical Management; Collection; Data; Development; Disease; Europe; Event; Eye; Functional disorder; Genes; Genetic; Glaucoma; Human; Iowa; Laboratories; Lead; Medical; Methods; Modeling; Molecular; Mus; Mutation; North America; Open-Angle Glaucoma; Pathogenesis; Pathway interactions; Patients; Pharmacologic Substance; Physiologic Intraocular Pressure; Population; Primary Open Angle Glaucoma; Proteins; Records; Regimen; Regulation; Research Design; Research Personnel; Resistance; Resources; Reticulum; Retinal Ganglion Cells; Rodent Model; Role; Sampling; Stress; Testing; Trabecular meshwork structure; Transgenic Mice; Universities; Vision; Work; axonal degeneration; base; biological adaptation to stress; design; endoplasmic reticulum stress; expectation; experience; improved; induced pluripotent stem cell; innovation; mouse model; myocilin; novel; novel strategies; novel therapeutics; pressure; protein misfolding; response; stem cell biology; stressor; treatment strategy

DESCRIPTION (provided by applicant): Glaucoma is second leading cause of irreversible blindness in the world affecting approximately 60 million people. Mutations in the gene encoding myocilin (MYOC) are responsible for most cases of juvenile onset glaucoma and 3-4% of adult onset primary open angle glaucoma. A number of laboratories have presented data demonstrating that mutations in MYOC result in retention of the protein in the endoplasmin reticulum (ER) and induction of ER stress responses. Using a novel transgenic mouse model we present functional data in this application to demonstrate that ER stress and subsequent activation of the Unfolded Protein Response (UPR) is a crucial step in the pathophysiology that leads to elevated IOP in myocilin-associated glaucoma. We further demonstrate that induction of UPR is sufficient to elicit IOP elevation in the absence of myocilin mutations. UPR is a general response to ER stress and can result from a variety of stressors, including mutations in other genes and environmental challenges. The proposed studies are based upon the hypothesis that mutations that result in protein misfolding in TM cells evoke chronic UPR, causing TM dysfunction and cell death, and ultimately result in IOP elevation. Therefore UPR may represent a general mechanism for elevation of IOP in POAG. The objective of this application is to determine whether UPR is a common mechanism leading to elevated IOP, not only in myocilin-associated glaucoma, but also in other types of primary open angle glaucoma. The proposed studies will be conducted using the exceptional resources available at the University of Iowa Glaucoma Center including the unique mouse model, our collection of several hundred well defined human donor eyes with and without glaucoma, excellent clinical resources, and expertise in the creation of human induced pluripotent stem cells. Confirmation of our hypothesis will not only identify the first cellular mechanism for the development of pathologically elevated IOP, but may also lead to novel medical approaches that could benefit millions of patients afflicted with POAG. PUBLIC HEALTH RELEVANCE: Glaucoma is a disease that causes vision loss and blindness in at least 3 million Americans and is associated with elevation of the intraocular pressure in the majority of glaucoma cases in North America and Europe. We have identified the first cellular mechanism that causes elevated pressure in a subset of patients. The proposed studies are designed to role of this mechanism in the overall glaucoma population. These data would significantly increase our understanding of the pathophysiology of the disease and provide novel targets for medical management of elevated intraocular pressure.

描述（由申请人提供）：青光眼是世界上不可逆失明的第二大主要原因，影响了约6000万人。编码肌动蛋白（MYOC）的基因中的突变是大多数青少年青光眼的大多数病例，成人发作初发角度的3-4％。许多实验室提出了数据，表明MYOC中的突变导致蛋白质在内胞浆网（ER）（ER）中保留并诱导ER应激反应。使用新型的转基因小鼠模型，我们在此应用中提出功能数据，以证明ER应力和随后的展开蛋白质反应（UPR）的激活是病理生理学的关键步骤，导致肌动蛋白相关的Glaucoma的IOP升高。我们进一步证明，在没有肌动蛋白突变的情况下，UPR的诱导足以引起IOP升高。 UPR是对ER应力的一般反应，可能是由多种压力源引起的，包括其他基因的突变和环境挑战。拟议的研究基于以下假设：TM细胞中蛋白质折叠的突变引起了慢性UPR，导致TM功能障碍和细胞死亡，并最终导致IOP升高。因此，UPR可能代表了IOP在POAG中升高的一般机制。该应用的目的是确定UPR是否是导致IOP升高的常见机制，不仅在与肌动蛋白相关的青光眼中，而且在其他类型的原发性敞开角度青光眼中。拟议的研究将使用爱荷华大学青光眼中心可用的特殊资源进行，包括独特的小鼠模型，我们收集了有或没有青光眼的几百个定义明确的人类供体眼，出色的临床资源以及在人类诱导的多能干细胞中创造的专业知识。确认我们的假设不仅将确定病理升高IOP发展的第一个细胞机制，而且还可能导致新的医学方法，这些医学方法可能使数百万患有POAG的患者受益。 公共卫生相关性：青光眼是一种至少300万美国人的视力丧失和失明的疾病 北美和欧洲的大多数青光眼病例。我们已经确定了在一部分患者中导致压力升高的第一种细胞机制。拟议的研究旨在在整个青光眼人群中的作用。这些数据将大大提高我们对疾病的病理生理学的理解，并为眼内压力升高的医疗管理提供新的目标。