Genetic Modulators of Glaucoma

青光眼是世界上不可逆性失明的主要原因。当眼内压升高时， 是一个主要的危险因素，视网膜神经节细胞（RGC）的损伤和死亡是视野丧失的基础。但 彻底了解这种疾病是一个重大的挑战，因为它的遗传基础是异质性的， 代表了一个家族的年龄相关性疾病，由交叉基因调节的病理生理学 网络.我们建议继续使用BXD（C57 BL/6 x DBA/2 J）家族的重组近交（RI）系 作为遗传参考面板（GRP），并将我们的工作与人类全基因组关联联合收割机结合起来 研究（GWAS），以揭示和澄清视神经（ON）损伤的遗传异质性。我们 最近在眼内压（IOP）的调节中使用这种组合方法取得了成功。我们 非常适合采取下一步并应用这种方法来定义RGC损伤的细胞靶点 与死我们建议揭示与肿瘤相关的ON损伤的表型差异， 与IOP调节共有的共同潜在机制。我们的长期研究目标是 确定疾病机制并开发神经保护疗法以保护患者的视网膜健康， 青光眼的风险。我们的总体目标是确定新的基因产物和相关机制，导致 使用多维遗传分析、跨物种比较（小鼠， 大鼠和人），并使用新的鼠青光眼模型进行验证。我们的核心假设是， 导致青光眼相关内表型的过程，如IOP升高和ON损伤， 跨物种共享，物种比较可以揭示共同的潜在机制， 有效测试靶向青光眼疗法。在目前的调查中，我们进行了系统的 ON损伤的分析，以及额外的物种-大鼠。我们将挖掘IOP和ON的广泛数据库 我们在五个年龄组中对70多种BXD菌株产生的损害，目的是定义 青光眼的新模型这一建议的整体优势在于结合了尖端系统 遗传学方法，青光眼表型的物种比较，以及强大的跨学科团队， 包括在系统遗传学、青光眼、人类和大鼠GWAS方面具有丰富经验的研究人员， 先进的计算方法。为了验证我们的假设，我们将进行以下三项研究：1） 鉴定12号染色体上调节ON损伤的候选基因; 2）确定IOP的调节是否 和/或ON损伤在啮齿动物物种中共有;和3）鉴定新的自发性青光眼模型 通过我们对100个或更多BXD菌株的放大BXD GRP的综合分析。的成果 这些研究将确定新的基因和分子网络，这些基因和分子网络构成了脑胶质瘤相关表型的基础 并且还为将来的分析提供独特的青光眼模型。这些结果预计将从根本上 推进青光眼疾病机制领域的研究，实现靶向治疗开发。

Glaucoma is the leading cause of irreversible blindness in the world. While elevated intraocular pressure (IOP) is a major risk factor, damage and death of retinal ganglion cells (RGCs) underlies visual field loss. However, a thorough understanding of this disease is a major challenge because its genetic basis is heterogeneous and it represents a family of age-related disorders resulting from intersecting gene-regulated pathophysiologic networks. We propose to continue to use the BXD (C57BL/6 x DBA/2J) family of recombinant inbred (RI) lines of mice as a genetic reference panel (GRP) and to combine our work with human genome wide association studies (GWAS), to uncover and clarify the genetic heterogeneity that underlies optic nerve (ON) damage. We have had recent success using this combined approach in the regulation of intraocular pressure (IOP). We are very well positioned to take the next step and apply this approach to define cellular targets of RGC damage and death. We propose to uncover phenotypic diversities of glaucoma-related ON damage and uncover common underlying mechanisms that are shared with IOP modulation. Our long-term research goal is to identify disease mechanisms and develop neuroprotective therapies to preserve retinal health in patients at risk for glaucoma. Our overall objective is to identify novel gene products and related mechanisms that lead to glaucomatous endophenotypes using multi-dimensional genetic analyses, cross-species comparisons (mouse, rat and human) and validation using novel murine glaucoma models. Our central hypothesis is that molecular processes leading to glaucoma associated-endophenotypes, such as elevated IOP and ON damage, are shared across species, and that species comparisons can uncover common underlying mechanisms, and efficient testing of targeted glaucoma therapeutics. In the current investigation, we perform a systematic analysis of ON damage, and an additional species—rat. We will mine the extensive databases of IOP and ON damage that we are generating for more than 70 BXD strains across five age cohorts with the goal of defining new models of glaucoma. An overall strength of this proposal is the combination of cutting-edge systems genetics methods, species comparisons of glaucoma phenotypes, and a strong interdisciplinary team that includes investigators with extensive experience in systems genetics, glaucoma, GWAS in human and rats, and advanced computational methods. To test our hypothesis, we will perform the following thress studies: 1) Identify the candidate gene on chromosome 12 that modulates ON damage; 2) Determine if modulation of IOP and/or ON damage is shared across rodent species; and 3) Identify novel spontaneous glaucoma models through a comprehensive analysis of our enlarged BXD GRP of 100 or more BXD strains. The outcomes of these studies will define novel genes and molecular networks that underlie glaucoma-associated phenotypes and also provide unique glaucoma models for future analysis. These results are expected to fundamentally advance the field of glaucoma disease mechanisms and enable targeted therapeutic development.