Metabolomic and Genetic Interactions in Age-Related Macular Degeneration

项目摘要 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）仍然是老年性黄斑变性的主要原因。 老年人不可逆转的失明。当前治疗模式的转变将需要更多 敏感的方法来识别疾病发展、进展和不良反应风险最大的患者， 治疗反应。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，而且还包括个人 毒素，药物，膳食补充剂，甚至食物的代谢。的确， 测量液体或组织中的代谢物已经成功地识别出其它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以下因素的影响： 遗传因素因此，我们的长期目标是开发结合遗传和代谢因素的图谱， 预测疾病风险和治疗反应，以改善AMD患者的临床结局。的 该建议的目的更集中于：辨别与AMD发病机制相关的代谢谱， 确定它们与AMD相关遗传变异的关系。我们的核心假设是， 与遗传变异相结合的特征驱动个体的AMD发展、进展和 对治疗的反应使用高分辨率液相色谱-质谱（LC-MS）和 基于序列的基因分型，我们将在两个已建立的独立队列中检验这一假设，沿着 从范德比尔特眼科研究所招募的新的前瞻性患者队列。在目标1中，测量血浆 AMD患者和对照组的代谢物将告诉我们这些组之间的代谢差异， 不同阶段的AMD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点。在目标2中，我们将联合收割机 已知AMD风险基因的基因型的代谢谱，以确定代谢物和基因变异如何 相互作用以影响AMD的发展和进展。这种方法将使我们从分子上深入了解 患者之间疾病进展的变异性。最后，目标3将前瞻性地评估 代谢和遗传特征对中度AMD进展和NVAMD治疗反应的影响。成功 这些目标的完成将提供与AMD相关的代谢变化的关键知识， 有助于识别疾病进展风险最大和治疗反应较差的患者。

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.