Discovery Approach to Ocular Hypertension

高眼压症的发现方法

• 批准号: 9333672
• 负责人: M. Elizabeth Fini
• 金额: $ 59.65万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333672
• 关键词: Acetates; Anti-Inflammatory Agents; Anti-inflammatory; Bioinformatics; Biological; Blindness; Blood specimen; Clinical; Cohort Studies; Collection; Corneal Endothelium; Corneal dystrophy; Custom; DNA; DNA analysis; DNA sequencing; Data; Descemet' s membrane; Disease; Effectiveness; Enhancement Technology; Enrollment; Eye; Eye diseases; Functional disorder; Funding; Genes; Genetic; Genetic study; Genomic Hybridizations; Genotype; Glaucoma; Glucocorticoids; Healthcare; Hybrids; Investigation; Keratoplasty; Knowledge; Los Angeles; Medical; Molecular Biology; Mucins; Ocular Hypertension; Operative Surgical Procedures; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Physiologic Intraocular Pressure; Primary Open Angle Glaucoma; Publishing; Quantitative Trait Loci; Refractory; Registries; Regulation; Research; Resources; Risk Factors; Saliva; Sampling; Steroids; Tail; Testing; Time; United States National Institutes of Health; Ursidae Family; Vision; Work; base; bead chip; blind; clinical practice; cohort; experimental study; follow-up; gene function; genetic approach; genetic variant; genome sequencing; innovation; new therapeutic target; novel; novel therapeutics; precision medicine; prednisolone; rare variant; therapeutic target; trait; whole genome

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.

7.项目总结/摘要 该申请提出了一种创新的和强大的多维方法来发现新的基因， 可能作为高眼压（OH）治疗靶点的通路。它关注的是一种次级形式 糖皮质激素（GC）治疗引起的OH。GC用于治疗多种疾病， 包括许多眼疾。然而，缺点是在眼睛中使用GC会导致潜在的视力下降。 高达一半的患者存在眼内压（IOP）升高的危险。这是由基因决定的，因此， 类固醇诱导的OH（SIOH）可以使用遗传学方法进行研究， 知识SIOH的病理生理学与一种更常见的OH形式相似， 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 与开角型青光眼相比，开角型青光眼具有观察期短得多、效应量大得多的优点。因此 对SIOH的研究可以发现其他方式无法揭示的途径。 此外，对SIOH的敏感性对于研究其本身是重要的，因为它限制了非常有效的 发现的一类抗炎药和遗传变异可能被预测性地用于制造类固醇 对患者更安全。在多年的工作中，多个PI已经证明了 以及他们发现新基因和途径的方法的有效性，其中一些代表了 有望成为新的治疗靶点现在，他们已经准备好进行全面的发现工作， 大型临床实践的领导者利用人口统计学上同质的Fuch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，所有患者均以高度统一的方式接受治疗， 术后GC，仔细进行术前表征和术后IOP随访。因此该 队列已完全分型。此外，许多患者已参加NIH资助的遗传学研究 这意味着已经收集了许多DNA样本。在计划的研究中， GC治疗后IOP的变化（Δ IOP）将作为定量特征，与之前的研究一样， 团队DNA测序将被添加到基于微阵列的基因分型中，以增加发现 罕见的基因变异与此同时，研究小组将继续跟进，增加新的线索，因为他们 起来。具体目的如下：1）完整收集DNA; 2）进行杂交基因组学研究; 分析，将微阵列基因分型与全基因组测序相结合; 3）识别基因组变异 数量性状的统计学相关性; 4）研究最高数量性状的功能意义 基因座和相关基因。应用这里概述的多维方法预计将有很高的 影响，从而推动视力保健领域精准医疗的发展。