A New Model of Human Primary Open-Angle Glaucoma

描述（由申请人提供）：眼内压（IOP）升高是青光眼发生和进展的一个致病风险因素。已经确定了几种新的致病途径，导致原发性开角型青光眼。青光眼突变Myocilin（MYOC）损伤小梁网并升高人类和小鼠的IOP。促纤维化细胞因子TGF <$2的房水水平在POAG患者中升高，并且TGF <$2升高灌注培养的前段和啮齿动物眼中的IOP。青光眼的动物模型对于发现和更好地理解分子致病途径以及测试新的青光眼治疗方法是重要的。虽然已经开发了许多不同的青光眼动物模型并进行了表征，但还没有真正的人POAG模型。我们的总体假设是，在小鼠眼中使用人POAG相关转基因（即突变MYOC和TGF？2）表达来升高IOP将导致小鼠的青光眼性视神经病变和视网膜病变。以下两个具体目标将解决并检验该假设：（SA #1）我们将进行有限的小鼠品系调查，以鉴定患有MYOC或TGF β 2诱导的高眼压的小鼠品系，其发展成青光眼性视神经病变和视网膜病变。(SA#2）一旦我们确定了敏感菌株，我们将通过评估视神经和RGC损伤并随时间（0-12周）测试视觉功能来进一步表征该菌株中的神经性昏迷损伤。人类POAG相关小鼠模型的开发将允许使用小鼠遗传学的力量对致病途径进行分子解剖，并为评估治疗青光眼的新治疗方法提供重要的新模型。 公共卫生相关性：在美国，青光眼是不可逆视力损害和失明的主要原因。眼压升高会损害眼睛后部的组织。这项研究将开发一种新的人类青光眼小鼠模型，这将使人们更好地了解疾病的过程，并提供一个合适的模型来测试新的青光眼疗法。

DESCRIPTION (provided by applicant): Elevated intraocular pressure (IOP) is a causative risk factor for the development and progression of glaucoma. Several new pathogenic pathways have been identified that cause primary open-angle glaucoma. Glaucomatous mutations in Myocilin (MYOC) damage the trabecular meshwork and elevate IOP in humans and in mice. Aqueous humor levels of the pro-fibrotic cytokine TGF¿2 are elevated in POAG patients, and TGF¿2 elevates IOP in perfusion cultured anterior segments and in rodent eyes. Animal models of glaucoma are important to discover and better understand molecular pathogenic pathways and test new glaucoma therapeutics. Although a number of different animal models of glaucoma have been developed and characterized, there are no true models of human POAG. Our overall hypothesis is that using human POAG relevant transgene (i.e. mutant MYOC and TGF¿2) expression in mouse eyes to elevate IOP will cause glaucomatous optic neuropathy and retinopathy in mice. The following two specific aims will address and test this hypothesis: (SA#1) We will conduct a limited mouse strain survey to identify a mouse strain(s) with MYOC- or TGF¿2-induced ocular hypertension that develops glaucomatous optic neuropathy and retinopathy. (SA#2) Once we have identified a sensitive strain, we will further characterize glaucomatous damage in this strain by assessing optic nerve and RGC damage and testing visual functions over time (0-12 weeks). The development of a relevant mouse model of human POAG will allow the molecular dissection of pathogenic pathways using the power of mouse genetics as well as provide an important new model for assessing new therapeutic approaches for the treatment of glaucoma. PUBLIC HEALTH RELEVANCE: Glaucoma is a leading cause of irreversible visual impairment and blindness in the United States. Elevated eye pressure damages tissues in the back of the eye. This study will develop a new mouse model of human glaucoma, which will allow a better understanding of the disease process and provide an appropriate model to test new glaucoma therapies.