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Mechanistically linking AMD, glycemic index and protein homeostasis

AMD、血糖指数和蛋白质稳态的机制联系

基本信息

批准号：
8526468
负责人：
ALLEN TAYLOR
金额：
$ 37.54万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8526468
关键词：
Address Advanced Glycosylation End Products Affect Age Age related macular degeneration Aging Animal Model Animals Appearance Area Biochemical Biological Models Blindness Blood Blood Glucose Bruch&apos s basal membrane structure Carbohydrates Cells Charge Control Animal Data Development Diet Dietary Carbohydrates Dietary Intervention Dietary Practices Discipline Disease Drusen Eating Elderly Enhancers Epidemiology Etiology Food Fright Future Glucose Glycemic Index Goals Health Health Benefit Health Care Costs Heart Diseases Homeostasis Human Human Resources Intake Intervention Intervention Trial Learning Lesion Link Literature Lysosomes Measures Modeling Modification Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nutraceutical Oxygen Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Population Post-Translational Protein Processing Proteins Proteolysis Publishing Quality Control Quality of life Reporting Research Retina Retinal Risk Sample Size Simulate Staging Stress System Testing Therapeutic Time Tissues Training Ubiquitin United States National Institutes of Health Vision Work age related base cohort cost cytotoxic design disorder risk epidemiologic data feeding food standard glycation in vivo interest mouse model multicatalytic endopeptidase complex novel prevent research study response sugar

项目摘要

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.

描述（由申请人提供）：视力丧失是老年人的主要恐惧，对生活质量有重大影响。视网膜相关性黄斑变性（AMD）是不可逆性失明的最常见原因。这种毁灭性的疾病无法治愈。仅在美国，与AMD相关的成本每年就达数十亿美元。当务之急是尽快找到延缓AMD发病或进展的方法，因为受影响的人数增长如此迅速。来自三个大型人类队列的新信息表明，食用较低血糖指数饮食（GI）与所有级别的AMD以及早期AMD延迟发作或进展的风险较低相关。这些信息表明，稍微限制容易消化的碳水化合物的摄入，或模拟这种饮食习惯，可能提供一种延迟AMD所有阶段的发作和进展甚至预防AMD的方法。减缓AMD进展，特别是在早期阶段，仅10-20%可以延迟视力丧失5-10年。在开始昂贵的干预试验之前，必须在对照动物试验中复制这些发现，并了解低GI饮食如何保护视网膜的机制。我们的试点动物研究表明，消费较低的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，生物化学研究表明，通常消除细胞毒性蛋白质的细胞蛋白水解能力受到糖化的损害。为了利用这些数据，关键是要了解消耗高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，蛋白水解机制的保真度之间的病理生化关系。在这项工作中，我们将测试的假设，即早期AMD样病变将被延迟，应激减少，蛋白水解功能，消除糖化蛋白保留在小鼠消耗较低的GI饮食或当激活剂的泛素或溶酶体蛋白水解途径。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。这些信息对于设计新的干预措施（饮食和药物）也至关重要，这将减少AMD的负担。第一个目的是确定饮食GI、早期AMD病变风险和蛋白质糖化之间的关系。由于AMD与RPE及其周围的蛋白质质量受损有关，因此目标2的重点将是使用来自动物模型的RPE和分化的RPE来定义糖化蛋白质积累与蛋白质质量控制机制的保真度之间的关系的新实验。在目标3中，我们将尝试新的药物来减少碳水化合物引起的压力和延长视网膜功能。由于许多细胞对应激反应的相似性以及许多细胞中类似的蛋白质质量控制，预计我们的观察和发现将影响许多学科并具有重大的健康影响。这包括心脏病和2型糖尿病，两者都与饮食碳水化合物摄入有关。