Discovery Approach to Ocular Hypertension

高眼压症的发现方法

• 批准号: 9751867
• 负责人: M. Elizabeth Fini
• 金额: $ 59.29万
• 依托单位: TUFTS MEDICAL CENTER
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751867
• 关键词: Acetates; 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; Endothelium; Enhancement Technology; Enrollment; Eye; Eye diseases; Functional disorder; Funding; Genes; Genetic; Genetic study; Genomics; 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。项目摘要/摘要 该应用程序提出了一种创新且强大的多维方法，以发现新基因和 可以用作眼高血压的治疗靶标的途径（OH）。它专注于次要形式 由糖皮质激素（GC）治疗引起的OH。 GC用于治疗多种疾病， 包括许多眼病。然而，缺点是在眼睛中使用GC在潜在的意义上会导致 最多一半的患者的眼内压（IOP）威胁要增加。这是遗传确定的，因此 类固醇诱导的OH（SIOH）可以使用不需要先前生物学的遗传方法研究 知识。 SIOH的病理生理具有与更常见的OH形式的相似之处，该形式导致 初级开角绿色菜单（POAG），但SIOH也具有独特的特征。重要的是，SIOH有 比POAG较短的观察期和效应大小要大得多的优点。因此， 对SIOH的研究可以使发现不会揭示的任何其他方式的途径成为可能。 此外，对SIOH的敏感性本身重要，因为它限制了非常有效的有用性 发现的一类抗炎药和遗传变异可以预测地使用立体 使用更安全的患者。在多年来进行的工作中，多PIS证明了能力 他们在发现新基因和途径的方法中的有效性，其中一些代表 有希望的新治疗靶标。现在准备进行全面的发现工作，他们与 大型临床实践的领导者，利用独特的人口统计学统一的内皮群体 接受角膜移植的角膜营养不良（FECD）患者，均以高度均匀的方式与 手术后的GC，具有仔细的手术前表征和手术后的IOP随访。那 队列已经完全表型。此外，许多患者已入学 FECD的研究，这意味着已经收集了许多DNA样品。在计划的研究中，最大 GC治疗后IOP的变化（ΔIOP）将作为定量性状，如先前的研究 团队。 DNA测序将添加到基于微阵列的基因分型中，以增强发现的机会 罕见的遗传变异。同时，研究团队将继续进行后续行动，并增加新的潜在客户 出现。提出的特定目的如下：1）DNA的完整收集； 2）执行杂种基因组 分析，将微阵列基因分型与整个基因组测序结合在一起； 3）识别基因组变体 与定量性状相关的统计； 4）研究最高定量性状的功能意义 基因座和相关基因。预计此处概述的多维方法的应用将具有较高的 影响，导致视力医疗保健中精确医学的发展。