THE BIOLOGY AND UTILITY SIRT1- MEDIATED NEUROPROTECTION

生物学和实用性 SIRT1 介导的神经保护

• 批准号: 7085094
• 负责人: DAVID A. SINCLAIR
• 金额: $ 31.12万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085094
• 关键词: Alzheimer' s disease; DNA damage; Huntington' s disease; aging; amidohydrolases; antioxidants; cognition; cyclin dependent kinase; disease /disorder model; free radical oxygen; genetically modified animals; laboratory mouse; longevity; nerve /myelin protein; neural degeneration; neurogenetics; neuropathology; neuropharmacologic agent; neuroprotectants; pharmacokinetics; stilbenes

There is a significant unmet medical need for therapies to treat neurodegenerative disorders. Alzheimer's disease (AD) and Huntington's disease (HD), for example, have no cure or even an effective treatment. These two diseases alone cost the US healthcare system $100+ billion a year. SIRT1 is a member of the sirtuin family of NAD+-dependent deacetylases, which are thought to have evolved very early in life's history to enhance an organism's chances of surviving adversity and may underlie the neuroprotection and other health benefits provided by caloric restriction (CR). Hyperactivation of SIRT1 is responsible for the remarkable ability of neurons to survive long afer being cut in the case of the Wallerian mouse mutant (WldS). We and others have also found that SIRT1 protects neurons against death and dysfunction in models for HD, AD and ALS. Resveratrol (a SIRT1-activating molecule) or "STAC" can significantly delay neurodegeneration and cognitive decline in the p25-Tg mouse model of AD. Our lab has generated 20+ analogs of resveratrol, some of which have improved stability and potency. We have also generated the first SIRT1 tissue-specific inducible transgenic mouse. In this proposal, we will investigate the mechanism by which SIRT1 provides protection against neurodegeneration and test whether SIRT1 activation can delay the progression of different two neurodegenerative disorders, namely AD and HD using mouse genetic models. Preliminary experiments indicate that SIRT1 works by suppressing apoptosis and increasing DNA repair, the latter of which is emerging as a possible contributor to brain aging and a variety of neurodegenerative disorders. The STACs and SIRT1 transgenic animals we have generated place us in a unique position to be able to test these hypotheses. Lay description: Ten percent of Americans over the age of 65 suffer from Alzheimer's disease, a disease estimated to cost approximately $100 billion annually. The SIRT1 protein is considered by many to possibly be a master regulator of the body's innate defenses against disease and debilitation. SIRT1 is somehow able to keep neurons healthy and alive when they would otherwise die. We aim to uncover the mechanism by which S1RT1 protects neurons and to develop molecules that stimulate the SIRT1 protein and provide protection against a variety of neurodegenerative diseases.

对治疗神经退行性疾病的疗法有很大的未满足医疗需求。阿尔茨海默氏症 例如，疾病（AD）和亨廷顿氏病（HD）没有治愈甚至有效治疗。 仅这两种疾病就花费了美国医疗保健系统每年100亿美元。 SIRT1是 NAD+依赖性脱乙酰基酶的Sirtuin家族，人们认为这在人生历史的早期就发展起来了 为了增强生物体幸存的逆境的机会，并可能是神经保护和其他的基础 热量限制（CR）提供的健康益处。 SIRT1的过度激活负责 在Wallerian小鼠突变体的情况下，神经元生存的显着能力长期被切割 （WLDS）。我们和其他人还发现，SIRT1保护神经元免受死亡和功能障碍 高清，AD和ALS的模型。白藜芦醇（SIRT1激活分子）或“ STAC”可以显着延迟 AD的P25-TG小鼠模型的神经变性和认知下降。我们的实验室已经产生了20多个 白藜芦醇的类似物，其中一些提高了稳定性和效力。我们也生成了第一个 SIRT1组织特异性诱导转基因小鼠。在此提案中，我们将通过 哪个SIRT1提供了防止神经变性的保护，并测试SIRT1激活是否会延迟 使用小鼠遗传模型的两种神经退行性疾病的进展，即AD和HD。 初步实验表明SIRT1通过抑制凋亡和增加DNA修复而起作用， 后者正在成为导致大脑衰老和各种神经退行性的可能促成的人 疾病。我们已经产生的Stacs和Sirt1转基因动物将我们处于独特的位置 能够检验这些假设。 外表描述：65岁以上的美国人中有百分之十的美国人患有阿尔茨海默氏病，一种疾病 估计每年耗资约1000亿美元。许多人认为SIRT1蛋白可能是大师 人体对疾病和衰弱的天体防御措施的调节者。 SIRT1以某种方式保持 神经元在否则会死亡时就健康而活。我们的目的是发现 S1RT1保护神经元并开发刺激SIRT1蛋白的分子并提供保护 针对多种神经退行性疾病。