Mechanistically linking AMD, glycemic index and protein homeostasis

项目总结 老年性黄斑变性(AMD)是致盲的主要原因。有限的治疗方法可供 大多数AMD患者要求更多的治疗方法和更多的病理生理信息，以 导致新的药物治疗，以预防或阻止AMD。令人鼓舞的是，最近的流行病学文献表明 摄入较低的血糖指数(GI)饮食(LG)与AMD和AMD风险降低有关 人类的进步。值得关注的是，典型的美国高GI饮食(HG)的消费量是定量的 与AMD发病和进展的风险较高相关。总而言之，现有数据表明， 氧化和葡萄糖衍生的损伤(统称为糖化损伤)与 引起AMD的原因。我们公布的和初步的数据表明，有可能逮捕与AMD相关的 通过从HG饮食转向LG饮食，在早期阶段提供AMDf。我们需要蒙面、随机的临床 证明GI-AMD关系的研究，但由于对GI-AMD的了解不足，这些研究具有挑战性 相关的病理生理学，费用高，缺乏生物标志物，需要较长的病程。我们将解决 这些空洞同时也试图提高细胞保存能力，作为避免AMDf的一种新方法。在……里面 目的1，使用食用HG饮食的野生型小鼠模拟与以下因素相关的过度糖化损伤 AMD，我们将试图证明AMDf被延迟或被阻止，视觉功能因运动而延长 来降低GI饮食。为了减轻过度糖化应激造成的损害，我们还将过度表达 乙醛酶基因GLO1(一种解毒糖化损伤的主要酶)，并测试它是否可以防止 AMDF.在目标2中，我们将使用先进的小鼠和人类(比较)代谢数据来确定潜在的 AMDf的生物标志物，揭示饮食GI相关性AMD的途径和机制。这些生物标志物将 作为生物标记物，允许对需要改变饮食或治疗的情况进行“更早的警告”。在《目标3》中，我们将 确定如何以新的方式利用内源性保护能力来保护视网膜功能。我们 将使用FDA批准的两种药物阿卡波糖和依帕格列酮来减轻与HG相关的糖化应激 节食。我们还将加强泛素-蛋白酶体和自噬降解系统，以缓解 受损和糖化的细胞毒性蛋白或其前体的积累，从而降低 AMDF.总之，这项研究将有助于通过以下方式改善对AMD的理解和治疗 阐明饮食GI-AMD关系的病理生物学。通过实现这些目标，我们将 帮助实现NEI视网膜研究计划的目标：了解 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 开发新的治疗方法。此外，由于心血管疾病和糖尿病也与老年人较高的饮食GI有关 美式饮食的研究结果将具有广泛的适用性。

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.