Metabolomic and Genetic Interactions in Age-Related Macular Degeneration

年龄相关性黄斑变性的代谢组学和遗传相互作用

• 批准号: 8576080
• 负责人: Milam A Brantley
• 金额: $ 46.8万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8576080
• 关键词: Accounting; Age; Age related macular degeneration; Amino Acids; Angiogenesis Inhibitors; Biological Markers; Blindness; Chronic Disease; Clinic; Clinical; Data; Databases; Developed Countries; Development; Diabetes Mellitus; Disease; Disease Outcome; Disease Progression; Elderly; Exposure to; Exudative age-related macular degeneration; Eye; Food; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Health; Heart failure; Individual; Institutes; Investigation; Knowledge; Link; Liquid Chromatography; Liquid substance; Mass Spectrum Analysis; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolism; Metabolite Interaction; Methodology; Methods; Molecular; Monitor; Outcome; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Plasma; Population; Positioning Attribute; Recruitment Activity; Reliance; Resolution; Risk; Risk Assessment; Risk Factors; Sampling; Smoking; Staging; Testing; Therapeutic Intervention; Tissues; Toxin; Treatment Efficacy; Tyrosine; United States; Universities; Work; base; case control; cohort; dietary supplements; disorder risk; genetic profiling; genetic variant; improved; insight; liquid chromatography mass spectrometry; member; metabolomics; non-genetic; prospective; public health relevance; response; toxin metabolism; treatment response

PROJECT SUMMARY Despite recent advances in treatment, age-related macular degeneration (AMD) remains the leading cause of irreversible blindness in the elderly population. A shift in the current therapy paradigm will require more sensitive methods of identifying patients at greatest risk for disease development, progression, and poor treatment response. Previously-investigated genetic polymorphisms account for only a portion of AMD risk. Other factors include not only health risks, such as smoking and exposure to other toxins, but also individual metabolism of toxins, drugs, dietary supplements, and perhaps even food. Indeed, comprehensive measurement of metabolites in fluid or tissue has successfully identified risk factors for other chronic diseases, including heart failure, diabetes, and Parkinson's disease. Nevertheless, metabolism is influenced largely by genetic factors. Thus, our long-term goal is to develop profiles combining genetic and metabolic factors to predict disease risk and treatment response in order to improve clinical outcomes for AMD patients. The objective of this proposal is more focused: to discern metabolic profiles related to AMD pathogenesis and determine their relationship to AMD-related genetic variants. Our central hypothesis posits that metabolic profiles combined with genetic variation drive an individual's risk for AMD development, progression, and response to treatment. Using high-resolution liquid chromatography-mass spectrometry (LC-MS) and Sequenom-based genotyping, we will test this hypothesis in two established independent cohorts, along with a new prospective patient cohort recruited from the Vanderbilt Eye Institute. In Aim 1, measuring plasma metabolites in AMD patients and controls will tell us the metabolic differences between these groups and between different stages of AMD. These metabolic variances will point to molecules and pathways that are associated with AMD and could serve as targets for therapeutic intervention. In Aim 2, we will combine these metabolic profiles with genotypes for known AMD-risk genes to determine how metabolites and gene variants interact to influence AMD development and progression. This approach will give us molecular insight into the variability in disease progression among patients. Finally, Aim 3 will prospectively evaluate the impact of metabolic and genetic profiles on intermediate AMD progression and NVAMD treatment response. Successful completion of these aims will provide critical knowledge of metabolic changes associated with AMD and will help identify patients at greatest risk for disease progression and poor treatment response.

项目总结