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: 8717668
• 负责人: Milam A Brantley
• 金额: $ 45.86万
• 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/8717668
• 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; risk variant; 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）：尽管最近在治疗方面取得了进展，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。先前研究的遗传多态性仅占AMD风险的一部分。其他因素不仅包括健康风险，如吸烟和接触其他毒素，还包括毒素，药物，膳食补充剂，甚至食物的个人代谢。事实上，对液体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风险因素，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谱，以预测疾病风险和治疗反应，从而改善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谱，并确定其与AMD相关遗传变异的关系。我们的中心假设假定代谢谱与遗传变异相结合驱动个体的AMD发展、进展和对治疗的反应的风险。使用高分辨率液相色谱-质谱法（LC-MS）和基于测序的基因分型，我们将在两个已建立的独立队列中检验这一假设，沿着同时从范德比尔特眼科研究所招募一个新的前瞻性患者队列。在目标1中，测量AMD患者和对照者的血浆代谢物将告诉我们这些组之间以及AMD的不同阶段之间的代谢差异。这些代谢变化将指向与AMD相关的分子和途径，并可作为治疗干预的靶点。在目标2中，我们将联合收割机这些代谢谱与已知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影响AMD的发展和进展。这种方法将使我们从分子水平上了解患者疾病进展的变异性。最后，目标3将前瞻性评估代谢和遗传特征对中度AMD进展和NVAMD治疗反应的影响。这些目标的成功完成将提供与AMD相关的代谢变化的关键知识，并将有助于识别疾病进展和治疗反应不良风险最大的患者。