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.

项目摘要 尽管最近的治疗进展，但与年龄相关的黄斑变性（AMD）仍然是 老年人口不可逆转的失明。当前治疗范式的转变将需要更多 识别疾病发育，进展和较差风险的患者的敏感方法 治疗反应。以前对遗传多态性的研究仅占AMD风险的一部分。 其他因素不仅包括健康风险，例如吸烟和暴露于其他毒素，还包括个人 毒素，药物，饮食补充剂甚至食物的代谢。确实，全面 在液体或组织中代谢物的测量已成功鉴定出其他慢性疾病的危险因素， 包括心力衰竭，糖尿病和帕金森氏病。然而，新陈代谢在很大程度上受到影响 遗传因素。因此，我们的长期目标是开发将遗传和代谢因素结合到 预测疾病风险和治疗反应，以改善AMD患者的临床结果。这 该提案的目的更加集中：辨别与AMD发病机理和 确定它们与AMD相关遗传变异的关系。我们的中心假设认为代谢 概况与遗传变异相结合驱动个人的AMD发展，进展和 对治疗的反应。使用高分辨率液相色谱 - 质谱法（LC-MS）和 基于序列的基因分型，我们将在两个已建立的独立人群中检验这一假设， 从范德比尔特眼科研究所招募了新的潜在患者队列。在AIM 1中测量等离子体 AMD患者和对照组中的代谢物将告诉我们这些组和 在不同阶段的AMD之间。这些代谢差异将指向分子和途径 与AMD相关，可以作为治疗干预的靶标。在AIM 2中，我们将结合这些 具有针对已知AMD风险基因的基因型的代谢谱，以确定代谢产物和基因变异 相互作用以影响AMD的发展和进展。这种方法将使我们对分子见解 患者疾病进展的差异。最后，AIM 3将前景评估 中间AMD进展和NVAMD治疗反应的代谢和遗传谱。成功的 这些目标的完成将为与AMD相关的代谢变化提供批判性知识，并将 帮助确定患疾病进展和治疗反应不佳的风险最大的患者。