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.

治疗神经退行性疾病的治疗方法有很大的医学需求，但尚未得到满足。阿尔茨海默氏症 例如，阿尔茨海默病(AD)和亨廷顿病(HD)没有治愈的方法，甚至没有有效的治疗方法。 仅这两种疾病每年就花费美国医疗系统1000多亿美元。SIRT1是 Sirtuin家族依赖NAD+的脱乙酰酶，被认为在生命历史的非常早期就进化了 增加有机体在逆境中生存的机会，可能是神经保护和其他 卡路里限制(CR)提供的健康益处。SIRT1的过度激活是导致 在瓦勒小鼠突变体的情况下，神经元在被切断后长期存活的非凡能力 (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的影响 HD、AD和ALS的型号。白藜芦醇(一种SIRT1激活分子)或“STAC”可以显著延迟 P25-Tg小鼠AD模型中的神经退行性变和认知能力下降。我们的实验室已经产生了20多个 白藜芦醇的类似物，其中一些具有更好的稳定性和效力。我们还产生了第一个 SIRT1组织特异性诱导转基因小鼠。在这项建议中，我们将通过以下方式研究这一机制 哪种SIRT1对神经退行性变提供保护，并测试SIRT1激活是否可以延缓 利用小鼠遗传模型研究两种不同的神经退行性疾病，即AD和HD的进展。 初步实验表明，SIRT1通过抑制细胞凋亡和促进DNA修复而发挥作用， 后者可能是导致大脑老化和多种神经退行性变的原因 精神错乱。我们产生的STAC和SIRT1转基因动物使我们处于独特的地位 能够检验这些假说。 外行描述：65岁以上的美国人中有10%患有阿尔茨海默病，这是一种疾病 据估计，每年的成本约为1000亿美元。许多人认为SIRT1蛋白可能是一种主控蛋白 身体对疾病和虚弱的先天防御的调节器。SIRT1不知何故能够保持 神经元健康而又活着，否则它们就会死亡。我们的目标是揭示 S1RT1保护神经元，并开发刺激SIRT1蛋白的分子并提供保护 对抗多种神经退行性疾病。