The Role of Sirtuin 1 Deacetylase in Amyotrophic Lateral Sclerosis

描述(申请人提供)：这项拟议工作的目标是分析脱乙酰酶Sirtuin 1(SIRT1)在肌萎缩侧索硬化症(ALS)中的作用，并调查SIRT1靶标乙酰化的变化是否可能成为该疾病患者的有用生物标记物。SIRT1已被证明对包括阿尔茨海默氏症、帕金森氏症和亨廷顿病在内的许多神经退行性疾病具有保护作用，SIRT1的小分子激活剂和抑制剂已在美国和欧洲进入第一阶段和第二阶段临床试验。使用ALS转基因小鼠模型的初步结果表明，过表达SIRT1可能对运动神经元疾病具有保护作用，这种现象的机制正在研究中。将使用各种生化和分子技术来研究SIRT1是否通过去乙酰化PGC1pha、LXRbeta、TDP43和其他sirtuin靶点来影响ALS疾病的进展。此外，还将探讨SIRT1过表达对蛋白酶体功能的影响。由于所有ALS小鼠品系都建立了罕见的家族性突变疾病模型，我们还将分析临床尸检样本，以了解在小鼠研究中观察到的蛋白质变化是否可推广到散发性ALS患者。这里提出的工作将在伦纳德·瓜伦特博士的指导下进行，他在1999年发现了sirtuins与衰老之间的联系，并于次年第一个报告了其新的催化活性。Guarente实验室已经逐渐将重点从研究低等生物的寿命转移到sirtuin蛋白在神经退化、癌症和其他衰老疾病中的作用。申请者是医学博士/博士，拥有临床病理学委员会认证，并承诺在她的整个职业生涯中至少有80%的时间是作为一名研究人员。她目前担任布里格姆妇女医院(BWH)的讲师和麻省理工学院的博士后研究员。她的长期目标是领导一个实验室，利用小鼠模型和人类样本进行基础和翻译研究，以研究衰老引起的神经退行性疾病。预计该项目将对ALS的新诊断和治疗策略产生重要的见解，并将为候选人作为独立研究员的职业生涯做好准备。

DESCRIPTION (provided by applicant): The goal of this proposed work is to analyze the role of the deacetylase Sirtuin 1 (SIRT1) in Amyotrophic Lateral Sclerosis (ALS) and to investigate whether changes in the acetylation of SIRT1 targets may be a useful biomarker in patients with this disease. SIRT1 has been shown to be protective in a number of neurodegenerative diseases including Alzheimer's, Parkinson's and Huntington's disease and small molecule activators and inhibitors of SIRT1 have entered phase I and phase II clinical trials the United States and Europe. Preliminary results using a transgenic mouse model for ALS indicate that overexpressing SIRT1 may be protective against motor neuron disease and the mechanism for this phenomenon is under investigation. A variety of biochemical and molecular techniques will be used to investigate whether SIRT1 affects ALS disease progression by deacetylating PGC1alpha, LXRbeta, TDP43 and other sirtuin targets. The effect of SIRT1 overexpression on proteasomal function will also be explored. Because all of the ALS mouse lines model rare familial mutations of the disease, we will also analyze clinical postmortem samples to learn whether protein changes observed in the mouse studies are generalizable to patients with sporadic ALS. The work proposed here will be conducted under the mentorship of Dr. Leonard Guarente, who discovered the link between sirtuins and aging in 1999 and was the first to report its novel catalytic activity the following year. The Guarente laboratory has gradually shifted its focus from studies on lifespan in lower organisms to the role of the sirtuin proteins in neurodegeneration, cancer and other diseases of aging. The applicant is an M.D. /Ph.D. who is board certified in clinical pathology and committed to spending a minimum of 80% of her time as a researcher throughout her career. She currently holds a joint appointment as instructor at Brigham and Women's Hospital (BWH) and postdoctoral affiliate at MIT. Her long-term goal is to direct a laboratory that performs basic and translational research using mouse models and human samples to study neurodegenerative diseases of aging. It is anticipated that the project will yield important insight into new diagnostic and therapeutic strategies for ALS and will prepare the candidate for a career as an independent investigator.