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: 9302786
• 负责人: Milam A Brantley
• 金额: $ 46.11万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 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/9302786
• 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; 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; genotyped patients; improved; insight; liquid chromatography mass spectrometry; member; metabolic profile; metabolomics; non-genetic; prospective; risk variant; targeted treatment; toxin metabolism; treatment response

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：尽管治疗方面最近取得了进展，但年龄相关性黄斑变性（AMD）仍然是老年人群中不可逆失明的主要原因。当前治疗模式的转变将需要更灵敏的方法来识别疾病发生、进展和治疗反应不良风险最大的患者。先前研究的基因多态性仅占 AMD 风险的一部分。其他因素不仅包括健康风险，例如吸烟和接触其他毒素，还包括毒素、药物、膳食补充剂甚至食物的个体代谢。事实上，对体液或组织中代谢物的全面测量已经成功地确定了其他慢性疾病的危险因素，包括心力衰竭、糖尿病和帕金森病。然而，新陈代谢在很大程度上受到遗传因素的影响。因此，我们的长期目标是开发结合遗传和代谢因素的档案来预测疾病风险和治疗反应，以改善 AMD 患者的临床结果。该提案的目标更加集中：辨别与 AMD 发病机制相关的代谢特征，并确定它们与 AMD 相关遗传变异的关系。我们的中心假设认为，代谢特征与遗传变异相结合会增加个体发生 AMD 的风险、进展和治疗反应。使用高分辨率液相色谱-质谱法 (LC-MS) 和基于 Sequenom 的基因分型，我们将在两个已建立的独立队列以及从范德比尔特眼科研究所招募的新前瞻性患者队列中测试这一假设。在目标 1 中，测量 AMD 患者和对照组的血浆代谢物将告诉我们这些组之间以及 AMD 不同阶段之间的代谢差异。这些代谢差异将指向与 AMD 相关的分子和途径，并可作为治疗干预的目标。在目标 2 中，我们将这些代谢谱与已知 AMD 风险基因的基因型相结合，以确定代谢物和基因变异如何相互作用以影响 AMD 的发生和进展。这种方法将使我们能够从分子角度了解患者疾病进展的变异性。最后，Aim 3 将前瞻性评估代谢和遗传特征对 AMD 中期进展和 NVAMD 治疗反应的影响。成功完成这些目标将提供与 AMD 相关的代谢变化的重要知识，并将有助于识别疾病进展和治疗反应不佳风险最大的患者。