A New Model of Human Primary Open-Angle Glaucoma

描述(由申请人提供)：高眼压(IOP)是青光眼发生和发展的致病危险因素。已发现几种新的致病途径可导致原发性开角型青光眼。在人类和小鼠中，青光眼肌钙蛋白(myocin，MYOC)基因突变破坏了小梁网络并升高了眼压。POAG患者房水中促纤维化细胞因子转化生长因子2水平升高，并且转化生长因子2升高了眼球前段和啮齿动物眼的眼压。青光眼的动物模型对于发现和更好地了解青光眼的分子致病途径以及测试新的青光眼治疗方法具有重要意义。虽然已经建立了许多不同的青光眼动物模型并确定了其特征，但还没有真正的人类POAG模型。我们的总体假设是，利用人POAG相关转基因(即突变型MYOC和转化生长因子2)在小鼠眼内表达来提高眼压将导致小鼠青光眼视神经病变和视网膜病变。以下两个特定目标将解决和验证这一假设：(SA#1)我们将进行一项有限的小鼠品系调查，以确定患有MYOC或TGF2诱导的高眼压的小鼠品系(S)，该品系会发展为青光眼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损伤并测试一段时间(0-12周)的视觉功能来进一步表征该菌株的青光眼损害。相关的人类POAG小鼠模型的建立将使利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方法提供一个重要的新模型。

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.