The Role of Sirtuin 1 Deacetylase in Amyotrophic Lateral Sclerosis

描述（由申请人提供）：这项拟议工作的目标是分析去乙酰化酶Sirtuin 1（SIRT 1）在肌萎缩侧索硬化症（ALS）中的作用，并研究SIRT 1靶标的乙酰化变化是否可能是该疾病患者的有用生物标志物。SIRT 1已被证明在许多神经退行性疾病中具有保护作用，包括阿尔茨海默氏病、帕金森氏病和亨廷顿氏病，并且SIRT 1的小分子激活剂和抑制剂已进入美国和欧洲的I期和II期临床试验。使用ALS转基因小鼠模型的初步结果表明，过表达SIRT 1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SIRT 1是否通过使PGC 1 α、LXR β、TDP 43和其他sirtuin靶点脱乙酰化来影响ALS疾病进展。SIRT 1过表达对蛋白酶体功能的影响也将被探讨。由于所有ALS小鼠系都是该疾病的罕见家族突变模型，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和衰老之间的联系，并在第二年第一个报告了其新颖的催化活性。Guarente实验室逐渐将重点从研究低等生物的寿命转移到sirtuin蛋白在神经退行性疾病，癌症和其他衰老疾病中的作用。申请人是一名医学博士。/博士她拥有临床病理学委员会认证，并承诺在整个职业生涯中至少有80%的时间是作为研究人员。她目前在布里格姆妇女医院（BWH）和麻省理工学院博士后附属机构担任讲师。她的长期目标是指导一个实验室，使用小鼠模型和人类样本进行基础和转化研究，以研究衰老的神经退行性疾病。预计该项目将对ALS的新诊断和治疗策略产生重要的见解，并为候选人作为独立研究者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.