Mechanistically linking AMD, glycemic index and protein homeostasis

描述(由申请人提供)：失明是老年人的一大恐惧，也是对生活质量的严重损害。老年性黄斑变性(AMD)是导致不可逆性失明的最常见原因。这种毁灭性的疾病是无法治愈的。仅在美国，与AMD相关的成本就高达每年数十亿美元。当务之急是尽快发现延缓AMD发病或进展的手段，因为受影响的人数增长如此之快。来自三个大型人类队列的新信息表明，食用较低的血糖指数饮食(GI)与所有级别的AMD以及延迟发病或进展的早期AMD的风险较低相关。这一信息表明，稍微限制易消化碳水化合物的摄入量，或模拟这种饮食习惯，可能会提供一种方法来延缓AMD所有阶段的发病和进展，甚至预防它。延缓AMD的进展，特别是在早期阶段，只需10%-20%就可以推迟5-10年的视力丧失。在开始昂贵的干预试验之前，有必要在对照动物试验中复制这些发现，并了解摄入较低GI饮食如何保护视网膜的机制。我们的试验性动物研究表明，摄入较低的GI饮食会导致早期AMD相关视网膜损伤的延迟积累。这也与糖(糖基化)对蛋白质的修饰较少有关。糖化蛋白是有毒的，与AMD的发展有关。此外，生化研究表明，正常情况下消除细胞毒性蛋白的细胞蛋白分解能力会因糖基化而受损。为了利用这些数据，了解进食更高GI饮食、AMD相关早期病变的出现、细胞毒性糖化蛋白的积累以及蛋白质编辑和蛋白质分解机制的保真度之间的病理生化关系是至关重要的。在这项工作中，我们将测试这一假说，即早期AMD样损害将延迟，糖化应激减弱，并在消耗较低GI饮食的小鼠中或在使用泛素或溶酶体蛋白分解途径的激活剂时，去除糖化蛋白的蛋白分解功能。这些病因和机制信息将证实低GI饮食的好处，并为干预试验铺平道路。这些信息对于设计新的干预措施(饮食和药物)也至关重要，这些干预措施将减轻AMD的负担。第一个目标是确定饮食GI、AMD早期损害风险和蛋白质糖化之间的关系。由于AMD与RPE及其周围环境中受损的蛋白质质量有关，因此Aim 2的重点将是利用动物模型的RPE和分化的RPE进行新的实验，以确定糖化蛋白质的积累与蛋白质质量控制机制的保真度之间的关系。在目标3中，我们将尝试新药来减轻碳水化合物引起的压力并延长视网膜功能。由于许多细胞对糖化应激的反应相似，许多细胞的蛋白质质量控制也相似，预计我们的观察和发现将影响许多学科，并对健康产生重大影响。这包括心脏病和2型糖尿病，这两种疾病都与饮食中的碳水化合物摄入量有关。

DESCRIPTION (provided by applicant): Loss of sight is a major fear and significantly compromise to the quality of life among the elderly. Age-related macular degeneration (AMD) is the most common cause of irreversible blindness. There is no cure for this devastating disease. Costs associated with AMD are in the $billions per year in the US alone. It is imperative that means to delay the onset or progress of AMD be found soon because the number of people afflicted is growing so rapidly. New information from three large human cohorts indicates that consuming lower glycemic index diets (GI) is associated with a lower risk for all grades of AMD as well as for delayed onset or progress of early AMD. This information suggests that slightly limiting intake of readily digested carbohydrate, or simulating such dietary practice, may provide a means to delay the onset and progress of all stages of AMD or even prevent it. Slowing AMD progression, particularly at early stages, by as little as 10-20% can delay vision loss for 5-10 years. Prior to initiating costly intervention trials, it is essential to replicate these findings in controlled animal trials and learn about the mechanism of how consuming lower GI diets protects the retina. Our pilot animal studies indicate that consuming lower GI diets results in delayed accumulation of early AMD-related retina lesions. This is also associated with less protein modification by sugars (glycation). Glycated proteins are toxic and related to AMD development. Furthermore, biochemical studies indicate that the cellular proteolytic capacities that normally eliminate cytotoxic proteins are compromised by glycation. In order to exploit these data, it is crucial to understand the patho-biochemical relationship between consuming higher GI diets, appearance of early AMD-related lesions, accumulation of cytotoxic glycated proteins, and the fidelity of the protein editing, proteolytic machinery. In this work we will test the hypothesis that early AMD-like lesions will be delayed, glycative stress diminished, and proteolytic functions that remove glycated proteins retained in mice that consume lower GI diets or when activators of the ubiquitin or lysosomal proteolytic pathways are employed. Such etiologic and mechanistic information will substantiate the benefit of lower GI diets and pave the way for intervention trials. The information is also essential for designing new interventions (dietary and pharmaceutical) that will diminish the AMD burden. The first Aim is to define the relationship between dietary GI, risk for early AMD lesions, and protein glycation. Because AMD is related to compromised protein quality in the RPE and its environs, the focus of Aim 2 will be novel experiments to define relationships between accumulation of glycated proteins and the fidelity of the protein quality control machinery, using RPE from the animal models and differentiated RPE. In Aim 3 we will try new drugs to diminish carbohydrate-induced stress and prolong retinal function. Due to the similarity of the response of many cells to glycative stress and the similar protein quality control in many cells it is anticipated that our observations and discoveries will impact many disciplines and have major health ramifications. This includes heart disease and type 2 diabetes, both of which have been related to dietary carbohydrate intake.