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.

对于治疗神经退行性疾病的疗法存在显着的未满足的医疗需求。阿尔茨海默氏症 例如，AD 和亨廷顿舞蹈病 (HD) 无法治愈，甚至没有有效的治疗方法。 仅这两种疾病每年就给美国医疗保健系统造成 1000 多亿美元的损失。 SIRT1 是以下组织的成员 Sirtuin 家族的 NAD+ 依赖性脱乙酰酶，被认为在生命历史的早期就已进化 提高有机体在逆境中生存的机会，并可能是神经保护和其他功能的基础 热量限制 (CR) 带来的健康益处。 SIRT1 的过度激活是造成 在华勒小鼠突变体中，神经元在被切割后仍能长时间存活的能力非常出色 （世界）。我们和其他人还发现 SIRT1 可以保护神经元免于死亡和功能障碍 HD、AD 和 ALS 型号。白藜芦醇（一种 SIRT1 激活分子）或“STAC”可以显着延迟 AD 的 p25-Tg 小鼠模型中的神经退行性变和认知能力下降。我们的实验室已生成 20 多个 白藜芦醇的类似物，其中一些具有改善的稳定性和效力。我们还生成了第一个 SIRT1 组织特异性诱导转基因小鼠。在本提案中，我们将通过以下方式研究该机制： SIRT1 提供针对神经退行性变的保护并测试 SIRT1 激活是否可以延迟 使用小鼠遗传模型研究不同两种神经退行性疾病（即 AD 和 HD）的进展。 初步实验表明，SIRT1通过抑制细胞凋亡和增加DNA修复来发挥作用， 后者可能是导致大脑衰老和各种神经退行性疾病的原因之一 失调。我们培育的 STAC 和 SIRT1 转基因动物使我们处于独特的地位 能够检验这些假设。 简单描述：65 岁以上的美国人中有 10% 患有阿尔茨海默病 估计每年花费约1000亿美元。许多人认为 SIRT1 蛋白可能是大师 调节人体对疾病和虚弱的先天防御能力。 SIRT1 能够以某种方式保留 神经元健康活跃，否则就会死亡。我们的目标是揭示其中的机制 S1RT1 保护神经元并开发刺激 SIRT1 蛋白并提供保护的分子 对抗多种神经退行性疾病。