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. 项目总结/文摘