Unfolded Protein Response in Glaucoma Pathogenesis

描述（由申请人提供）：青光眼是世界上不可逆失明的第二大原因，影响约6000万人。编码myocilin（MYOC）的基因突变是大多数青少年型青光眼和3-4%成人型原发性开角型青光眼的原因。许多实验室已经提供了数据，证明MYOC突变导致蛋白质保留在内质网（ER）中并诱导ER应激反应。使用一种新的转基因小鼠模型，我们提出了在这个应用程序中的功能数据，以证明ER应激和随后的未折叠蛋白反应（UPR）的激活是导致肌球蛋白相关性青光眼IOP升高的病理生理学中的关键步骤。我们进一步证明，在没有肌球蛋白突变的情况下，诱导UPR足以引起IOP升高。 UPR是对ER应激的一般反应，可以由各种应激源引起，包括其他基因的突变和环境挑战。所提出的研究基于以下假设：导致TM细胞中蛋白质错误折叠的突变引起慢性UPR，导致TM功能障碍和细胞死亡，并最终导致IOP升高。因此，UPR可能是POAG眼压升高的一般机制。本申请的目的是确定UPR是否是导致IOP升高的常见机制，不仅在肌球蛋白相关性青光眼中，而且在其他类型的原发性开角型青光眼中。拟议的研究将使用爱荷华州大学青光眼中心的特殊资源进行，包括独特的小鼠模型，我们收集的数百个明确的人类供体眼睛（有或没有青光眼），优秀的临床资源和创造人类诱导多能干细胞的专业知识。证实我们的假设不仅将确定病理性IOP升高的第一个细胞机制，而且还可能导致新的医疗方法，使数百万患有POAG的患者受益。 公共卫生相关性：青光眼是一种在至少300万美国人中引起视力丧失和失明的疾病， 大多数青光眼病例发生在北美和欧洲。我们已经确定了第一个导致患者亚组血压升高的细胞机制。拟定的研究旨在研究该机制在整个青光眼人群中的作用。这些数据将显著增加我们对该疾病的病理生理学的理解，并为眼内压升高的医学管理提供新的靶点。

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.