Unfolded Protein Response in Glaucoma Pathogenesis

描述（由申请人提供）：青光眼是世界上第二大不可逆失明的原因，影响了大约6000万人。大多数青少年型青光眼和3-4%的成人型原发性开角型青光眼是由心肌蛋白（MYOC）编码基因突变引起的。许多实验室提供的数据表明，MYOC突变导致内质酶网（ER）中蛋白质的保留和内质酶网应激反应的诱导。使用一种新型转基因小鼠模型，我们在本应用程序中展示了功能数据，以证明内质网应激和随后的未折叠蛋白反应（UPR）的激活是导致肌素相关性青光眼IOP升高的病理生理学的关键步骤。我们进一步证明，在没有心肌蛋白突变的情况下，UPR的诱导足以引起IOP升高。UPR是对内质网应激的一般反应，可由多种应激源引起，包括其他基因突变和环境挑战。提出的研究基于这样的假设：导致TM细胞蛋白错误折叠的突变引起慢性UPR，导致TM功能障碍和细胞死亡，最终导致IOP升高。因此，UPR可能代表POAG患者IOP升高的一般机制。本应用的目的是确定UPR是否是导致IOP升高的共同机制，不仅在心肌素相关性青光眼中，而且在其他类型的原发性开角型青光眼中也是如此。拟议的研究将利用爱荷华大学青光眼中心的特殊资源进行，包括独特的小鼠模型，我们收集的数百只明确的有青光眼和无青光眼的人类供体眼睛，优秀的临床资源和创造人类诱导多能干细胞的专业知识。如果我们的假设得到证实，不仅可以确定病理性IOP升高的第一个细胞机制，还可能带来新的医学方法，使数百万POAG患者受益。

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.