Mechanistically linking AMD, glycemic index and protein homeostasis

AMD、血糖指数和蛋白质稳态的机制联系

• 批准号: 9789323
• 负责人: ALLEN TAYLOR
• 金额: $ 37.75万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789323
• 关键词: Acarbose; Address; Advanced Glycosylation End Products; Age related macular degeneration; Aging; American; American diet; Animal Experiments; Animal Model; Biochemical; Biological Markers; Blindness; Carbohydrates; Chromatin; Chronic; Clinical Research; Consumption; Data; Diabetes Mellitus; Diet; Drusen; Early Diagnosis; Early identification; Early treatment; Elderly; Enzymes; Epidemiology; Etiology; Excretory function; FDA approved; Food; Functional disorder; Genes; Genetic; Glucose; Glycemic Index; Goals; Human; Human Characteristics; Impairment; Intake; Laboratories; Lactoylglutathione Lyase; Lead; Life; Link; Lipids; Literature; Masks; Medicine; Metabolism; Modeling; Modification; Molecular; Mus; Nature; Organism; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Proteins; Publishing; Pyruvaldehyde; Quality Control; Randomized; Randomized Clinical Trials; Reactive Oxygen Species; Research; Retina; Retinal; Risk; Role; Serum; Stress; System; Testing; Therapeutic Intervention; Tissues; Toxic effect; Translating; Ubiquitin; Vision; Western World; age related; base; comparative; cost; cytotoxic; diabetic; experimental study; glucose uptake; glycation; high risk; improved; insight; metabolome; metabolomics; multicatalytic endopeptidase complex; new technology; novel diagnostics; novel strategies; novel therapeutics; overexpression; potential biomarker; preservation; prevent; programs; proteostasis

PROJECT SUMMARY Age Related Macular Degeneration (AMD) is the major cause of blindness. The limited therapies available to the majority of AMD sufferers demand additional approaches and more pathophysiologic information that can lead to new drug treatments to prevent or arrest AMD. Encouragingly, recent epidemiologic literature indicates that consuming lower glycemic index (GI) diets (LG) is related to diminished risk for AMD and AMD progression in humans. Of concern, consumption of the typical American high GI diet (HG) is quantitatively associated with higher risk for onset and progress of AMD. Together, the available data indicate that excessive oxidative and glucose-derived damage (collectively called glycative damage) is associated with and is likely causative for AMD. Our published and preliminary data suggest that it may be possible to arrest AMD-related features (AMDf) at an early stage by switching from HG to LG diets. We need masked, randomized clinical studies to prove the GI-AMD relationship, but these are challenging due to insufficient understanding of the pathophysiology of the association, high cost, lack of biomarkers, and long duration required. We will address these voids while also attempting to enhance cellular preservation capacities as a new way to avoid AMDf. In Aim 1, using wildtype mice consuming HG diets to model the excessive glycative damage associated with AMD, we will seek to demonstrate that AMDf is delayed or arrested and visual function is prolonged by moving to lower GI diets. In order to mitigate damage caused by excessive glycative stress, we will also overexpress the glyoxalase gene GLO1 (a major enzyme that detoxifies glycative damage) and test whether it prevents AMDf. In Aim 2, we will use advanced mouse and human (comparative) metabolomic data to identify potential biomarkers of AMDf and reveal pathways and mechanisms of dietary GI-related AMD. These biomarkers will serve as biomarkers, allowing for “earlier warning” about the need dietary change or therapy. In Aim 3, we will determine how endogenous protective capacities can be exploited in new ways to preserve retinal function. We will use two FDA-approved drugs, acarbose and empagliflozin to diminish glycative stress associated with HG diets. We will also enhance the ubiquitin-proteasome and autophagic degradation systems in order to mitigate accumulation of damaged and glycated cytotoxic proteins or their precursors, thereby diminishing risk for AMDf. Together, this research will contribute to improved understanding of- and therapy for- AMD by elucidating the pathobiology of the dietary GI-AMD relationship. By accomplishing these objectives, we will help achieve the NEI retina research program's goal to “understand the molecular and biochemical bases for different forms of AMD, improve early diagnosis, characterize environmental effects on its etiology, and develop new treatments.” Moreover, since CVD and diabetes are also related to the higher dietary GI of the American diet, the findings will have broad applicability.

项目摘要 与年龄相关的黄斑变性（AMD）是失明的主要原因。有限疗法可用于 大多数AMD患者需要其他方法和更多的病理生理信息 导致新的药物治疗以防止或逮捕AMD。令人鼓舞的是，最近的流行病学文献表明 消耗低血糖指数（GI）饮食（LG）与AMD和AMD的风险降低有关 人类的进展。令人担忧的是，典型的美国高GI饮食（HG）的消费是定量的 与AMD的发作和进度更高的风险相关。一起，可用的数据表明超级 氧化和葡萄糖衍生的损伤（统称称为糖性损伤）与 AMD的病因。我们发布的初步数据表明，有可能逮捕与AMD相关的 在早期阶段的特征（AMDF）从HG转换为LG饮食。我们需要掩盖的随机临床 证明GI-AMD关系的研究，但由于对 协会的病理生理学，高成本，缺乏生物标志物以及需要长时间的持续时间。我们将解决 这些空隙同时还试图增强细胞保存能力，以避免AMDF。 AIM 1，使用野生型小鼠食用汞饮食来建模与 AMD，我们将寻求证明AMDF已被延迟或逮捕，并且通过移动来延长视觉功能 降低胃肠道饮食。为了减轻过度糖性压力造成的损害，我们还将过表达 乙二醇酶基因GLO1（一种排毒糖性损伤的主要酶）并测试它是否防止 AMDF。在AIM 2中，我们将使用高级鼠标和人类（比较）代谢组数据来识别潜力 AMDF的生物标志物，并揭示了与饮食GI相关的AMD的途径和机制。这些生物标志物会 用作生物标志物，允许“较早的警告”饮食变化或治疗。在AIM 3中，我们将 确定如何以新的方式探索内源性保护能力以保留残留功能。我们 将使用两种FDA批准的药物，acarbose和empagliflozin来减少与Hg相关的糖性胁迫 饮食。我们还将增强泛素 - 蛋白酶体和自噬降解系统，以减轻 累积受损和糖化的细胞毒性蛋白或其前体，从而降低了风险 AMDF。这项研究将共同​​有助于提高对治疗和治疗的理解。 阐明饮食GI-AMD关系的病理学。通过完成这些目标，我们将 帮助实现NEI Retina研究计划的目标，以“了解分子和生化基础 不同形式的AMD，改善早期诊断，表征环境对其病因的影响以及 此外，由于CVD和糖尿病也与较高的饮食GI有关 美国饮食，这些发现将具有广泛的适用性。