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）：视力丧失是一种主要的恐惧，并严重妥协了老年人生活质量。与年龄相关的黄斑变性（AMD）是不可逆的失明的最常见原因。这种毁灭性疾病无法治愈。与AMD相关的成本仅在美国每年数十亿美元。必须尽快延迟AMD的发作或进度，因为受伤的人数迅速增长，因此很快就会发现AMD的发作或进度。来自三个大型人类人群的新信息表明，消耗较低血糖指数饮食（GI）与所有AMD等级的风险较低以及AMD的延迟发作或进度有关。该信息表明，略微限制了容易消化的碳水化合物的摄入量或模拟这种饮食实践，可能会提供一种延迟AMD所有阶段的发作和进步甚至阻止它的方法。减慢AMD的进展，尤其是在早期阶段，低至10-20％可以延迟5 - 10年的视力损失。在启动昂贵的干预试验之前，必须在受控动物试验中复制这些发现，并了解消耗较低胃肠道饮食如何保护视网膜的机制。我们的试点动物研究表明，消耗较低的胃肠道饮食会导致早期与AMD相关的视网膜病变的积累延迟。这也与糖（糖基化）蛋白质修饰较少有关。糖化的蛋白质有毒，与AMD发育有关。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会因糖基化而损害。为了利用这些数据，了解消耗较高的胃肠道饮食，早期与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的忠诚度之间的病情生物化学关系至关重要。在这项工作中，我们将测试以下假设：早期类似AMD的病变将延迟，糖性胁迫减轻以及蛋白水解功能，这些功能消除了保留在较低胃肠道饮食的小鼠中或使用泛素或溶酶体蛋白水解途径的激活剂中的小鼠中。这种病因和机械信息将证实较低的胃肠道饮食的好处，并为干预试验铺平道路。该信息对于设计新的干预措施（饮食和药品）也至关重要，这些干预措施将减轻AMD负担。第一个目的是定义饮食中GI，早期AMD病变的风险和蛋白质糖化之间的关系。由于AMD与RPE及其周围环境中的蛋白质质量受损有关，因此AIM 2的重点将是定义糖化蛋白的积累与蛋白质质量控制机械的储蓄之间的关系，该实验是使用动物模型的RPE与蛋白质质量控制机械的忠诚度。在AIM 3中，我们将尝试使用新药来减轻碳水化合物诱导的应激和延长视网膜功能。由于许多细胞对糖性胁迫的反应相似，并且在许多细胞中的蛋白质质量控制的相似性，因此预计我们的观察结果和发现将影响许多学科并具有重大的健康后果。这包括心脏病和2型糖尿病，两者都与饮食中的碳水化合物摄入有关。