Discovery Approach to Ocular Hypertension

7.项目摘要/摘要 这项应用提出了一种创新和强大的多维方法来发现新的基因和 可作为治疗高眼压(OH)靶点的途径。它关注的是第二种形式 糖皮质激素(GCs)治疗引起的OH。GCS被用于治疗各种各样的疾病， 包括许多眼科疾病。然而，缺点是在眼睛中使用GC会导致潜在的视力 高达一半的患者存在眼压升高的危险。这是由基因决定的，因此， 类固醇诱导的OH(SIOH)可以用遗传方法进行研究，这种方法不需要事先的生物学研究 知识。SIOH的病理生理学与一种更常见的OH形式有相似之处，后者导致 原发性开角型青光眼(POAG)，但SIOH也有独特的特点。重要的是，SIOH拥有 与POAG相比，POAG的观测周期短得多，影响规模大得多。因此， 对SIOH的研究可能使发现其他任何方式都不可能揭示的路径成为可能。 此外，对SIOH的敏感性本身也很重要，因为它限制了非常有效的 已发现的一类抗炎药物和基因变异可能被预测用于制造类固醇 对患者使用更安全的。在多年来开展的工作中，多项指标已经证明了这种力量 以及他们发现新基因和途径的有效性，其中几个代表了 前景看好的新治疗靶点。现在，他们已经准备好进行全面的发现努力，他们已经与 大型临床实践的领导者利用人口统计上均一的Fuchs内皮细胞的独特队列 接受角膜移植的角膜营养不良(FECD)患者，都以高度统一的方式接受治疗 术后GCS评分、术前细致的眼压特征和术后眼压随访。因此，这就是 这群人已经完全表现出来了。此外，许多患者已经登记参加了一项由NIH资助的基因研究 对FECD的研究，意味着已经收集了许多DNA样本。在计划中的研究中，最大 GC治疗后眼压的变化(Δ眼压)将作为数量性状，与之前的研究一样 一队。DNA测序将添加到基于微阵列的基因分型中，以增加发现 罕见的基因变异。同时，研究小组将继续跟进，增加新的线索，因为他们 站起来。提出的具体目标如下：1)完全收集DNA；2)进行杂交基因组 分析，结合微阵列基因分型和全基因组测序；3)确定基因组变异 与数量性状相关的统计；4)研究顶级数量性状的功能意义 基因座和相关基因。这里概述的多维方法的应用预计将有很高的 影响，导致精准医学在视力保健领域的进步。

7. PROJECT SUMMARY/ABSTRACT This application proposes an innovative and powerful multidimensional approach to discover novel genes and pathways that may serve as therapeutic targets for ocular hypertension (OH). It focuses on a secondary form of OH caused by treatment with glucocorticoids (GCs). GCs are used to treat a wide variety of diseases, including many eye diseases. A drawback however, is that use of GCs in the eye results in a potentially sight threatening increase in intraocular pressure (IOP) in up to half of patients. This is genetically determined, thus, steroid-induced OH (SIOH) can be investigated using genetic approaches that requires no a prior biological knowledge. The pathophysiology of SIOH bears similarities to a much more common form of OH that leads to Primary Open Angle Glaucoma (POAG), but SIOH also has unique features as well. Importantly, SIOH has the advantages of a much shorter observation period and much larger effect sizes than POAG. Therefore, the study of SIOH could make it possible to discover pathways that would not have been revealed any other way. In addition, sensitivity to SIOH is important to study in its own right, as it limits the usefulness of a very effective class of anti-inflammatory drugs and genetic variants discovered might be used predictively to make steroid use safer for patients. In work conducted over a number of years, the multi-PIs have demonstrated the power and effectiveness of their approach for discovery of novel genes and pathways, several of which represent promising new therapeutic targets. Now ready for a full-fledged discovery effort, they have partnered with leaders of a large clinical practice to utilize a unique cohort of demographically homogenous Fuch's endothelial corneal dystrophy (FECD) patients that received corneal transplants, all treated in a highly uniform way with GCs following surgery, with careful pre-surgical characterization and post-surgical IOP follow-up. Thus this cohort is already fully phenotyped. Moreover, many patients have been enrolled in an NIH-funded genetic study of FECD, meaning many DNA samples have already been collected. In the planned study, the maximum change in IOP following GC treatment (ΔIOP) will serve as the quantitative trait, as in previous studies from this team. DNA sequencing will be added to microarray-based genotyping to enhance opportunity for discovery of rare genetic variants. At the same time the research team will continue follow-up, adding new leads as they arise. The proposed Specific Aims are as follows: 1) complete collection of DNA; 2) perform hybrid genomic analysis, combining microarray genotyping with whole genome sequencing; 3) identify genomic variants statistical associated with the quantitative trait; 4) investigate functional significance of the top quantitative trait loci and associated genes. Application of the multidimensional approach outlined here is predicted to have high impact, leading to the advancement of precision medicine in vision healthcare.