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，严重影响了他们的生活质量。年龄相关性黄斑变性（AMD）是不可逆失明的最常见原因。这种毁灭性的疾病无法治愈。仅在美国，与AMD相关的成本每年就高达数十亿美元。必须尽快发现延缓AMD发病或进展的方法，因为患病人数增长如此迅速。来自三个大型人类队列的新信息表明，食用低血糖指数饮食（GI）与所有级别AMD以及早期AMD延迟发病或进展的风险降低有关。这一信息表明，稍微限制易消化碳水化合物的摄入，或模拟这样的饮食习惯，可能提供一种延缓AMD所有阶段的发病和进展，甚至预防AMD的方法。减缓AMD的进展，特别是在早期阶段，只要10-20%就可以延缓视力丧失5-10年。在开始昂贵的干预试验之前，有必要在对照动物试验中重复这些发现，并了解食用低GI饮食如何保护视网膜的机制。我们的试点动物研究表明，食用低GI饮食导致早期amd相关视网膜病变的延迟积累。这也与糖（糖基化）较少的蛋白质修饰有关。糖化蛋白是有毒的，与AMD的发展有关。此外，生化研究表明，通常消除细胞毒性蛋白的细胞蛋白水解能力受到糖基化的损害。为了利用这些数据，了解高GI饮食、早期amd相关病变的出现、细胞毒性糖化蛋白的积累以及蛋白质编辑、蛋白质水解机制的保真度之间的病理生化关系至关重要。在这项工作中，我们将验证这样的假设，即早期amd样病变将被延迟，糖糖应激减少，并且当摄入低GI饮食或使用泛素或溶酶体蛋白水解途径的激活剂时，蛋白水解功能去除保留的糖基化蛋白。这些病因学和机制信息将证实低GI饮食的益处，并为干预试验铺平道路。这些信息对于设计减少AMD负担的新干预措施（饮食和药物）也是必不可少的。第一个目的是确定饮食GI、早期AMD病变风险和蛋白糖化之间的关系。由于AMD与RPE及其周围的蛋白质质量受损有关，Aim 2的重点将是利用来自动物模型的RPE和分化的RPE，进行新的实验，以确定糖化蛋白的积累与蛋白质质量控制机制的保洁度之间的关系。在第三阶段，我们将尝试新的药物来减少碳水化合物诱导的应激和延长视网膜功能。由于许多细胞对糖糖应激的反应和许多细胞中类似的蛋白质质量控制的相似性，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.