Unfolded Protein Response in Glaucoma Pathogenesis

描述(申请人提供)：青光眼是世界上影响约6000万人的第二大不可逆性失明原因。编码肌红素(MYOC)的基因突变是导致大多数青少年青光眼和3-4%成人起病的原发性开角型青光眼的原因。许多实验室提供的数据表明，MYOC的突变导致蛋白质保留在内质网(ER)中，并诱导内质网应激反应。利用一种新的转基因小鼠模型，我们在这一应用中提供了功能数据，以证明内质网应激和随后的未折叠蛋白反应(UPR)的激活是导致Myoclin相关性青光眼眼压升高的病理生理过程中的关键一步。我们进一步证明，在没有myoclin突变的情况下，诱导UPR足以引起眼压升高。UPR是对内质网应激的一种普遍反应，可由多种应激源引起，包括其他基因的突变和环境挑战。建议的研究是基于这样的假设，即导致TM细胞蛋白质错误折叠的突变会引起慢性UPR，导致TM功能障碍和细胞死亡，并最终导致眼压升高。因此，UPR可能是POAG眼压升高的一般机制。这项应用的目的是确定UPR是否是导致眼压升高的常见机制，不仅在霉菌素相关性青光眼中如此，在其他类型的原发性开角型青光眼中也是如此。拟议的研究将利用爱荷华大学青光眼中心现有的特殊资源进行，包括独特的小鼠模型、我们收集的数百只定义明确的患有和不患有青光眼的人类供体眼睛、出色的临床资源以及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高眼压发生的第一个细胞机制，而且还可能导致新的医学方法，可能使数百万患有POAG的患者受益。 公共卫生相关性：青光眼是一种疾病，在至少300万美国人中导致视力丧失和失明，并与眼压升高有关。 北美和欧洲的大多数青光眼病例。我们已经确定了导致部分患者血压升高的第一个细胞机制。拟议的研究旨在探讨这一机制在整个青光眼人群中的作用。这些数据将大大增加我们对这种疾病的病理生理学的了解，并为高眼压的医疗管理提供新的靶点。

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.