Mechanistically linking AMD, glycemic index and protein homeostasis

项目摘要 年龄相关性黄斑变性（AMD）是致盲的主要原因。有限的治疗方法， 大多数AMD患者需要额外的方法和更多的病理生理信息， 导致新的药物治疗来预防或阻止AMD。令人鼓舞的是，最近的流行病学文献表明， 消费较低的血糖指数（GI）饮食（LG）与降低AMD和AMD的风险有关。 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 与AMD发病和进展的风险较高相关。总的来说，现有数据表明， 氧化和葡萄糖衍生的损伤（统称为免疫损伤）与 导致AMD。我们发表的和初步的数据表明，它可能是可能的，以阻止AMD相关的 通过从HG饮食切换到LG饮食，在早期阶段改善AMDf特征。我们需要盲法随机临床试验 研究来证明GI-AMD的关系，但这些都是具有挑战性的，由于对 相关的病理生理学、高成本、缺乏生物标志物和需要长持续时间。我们将解决 这些空隙，同时也试图提高细胞的保存能力，作为一种新的方式，以避免AMDf。在 目的1，使用食用HG饮食的野生型小鼠来建立与 我们将试图证明，AMDf是延迟或逮捕和视觉功能延长移动 降低GI饮食。为了减轻过度应激造成的损害，我们还将过度表达 glycoprotein酶基因GLO 1（一种主要的酶，解毒的破坏），并测试它是否防止 AMDf。在目标2中，我们将使用先进的小鼠和人类（比较）代谢组学数据来确定潜在的 AMDf的生物标志物，并揭示饮食GI相关AMD的途径和机制。这些生物标志物将 作为生物标志物，允许“早期警告”需要改变饮食或治疗。在目标3中，我们 确定如何利用内源性保护能力以新的方式保护视网膜功能。我们 将使用两种FDA批准的药物阿卡波糖和恩格列净来减少与HG相关的应激反应 节食。我们还将加强泛素-蛋白酶体和自噬降解系统，以减轻 受损和糖化的细胞毒性蛋白质或其前体的积累，从而降低 AMDf。总之，这项研究将有助于改善对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， 帮助实现NEI视网膜研究计划的目标，以“了解分子和生物化学基础， 不同形式的AMD，改善早期诊断，表征环境对其病因的影响， 开发新的治疗方法。”此外，由于CVD和糖尿病也与较高的饮食GI有关， 美国人的饮食习惯，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.