The Role of Sirtuin 1 Deacetylase in Amyotrophic Lateral Sclerosis

描述（由申请人提供）：这项拟议工作的目的是分析去乙酰化酶SIRT1 （SIRT1）在肌萎缩性侧索硬化症（ALS）中的作用，并研究SIRT1靶点乙酰化的变化是否可能是该疾病患者有用的生物标志物。SIRT1已被证明对包括阿尔茨海默病、帕金森病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SIRT1可能对运动神经元疾病具有保护作用，这一现象的机制正在研究中。多种生化和分子技术将用于研究SIRT1是否通过去乙酰化pgc1 α、LXRbeta、TDP43和其他sirtuin靶点来影响ALS疾病进展。我们还将探讨SIRT1过表达对蛋白酶体功能的影响。因为所有的ALS小鼠系都模拟了罕见的ALS家族突变，我们还将分析临床死后样本，以了解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Leonard Guarente博士的指导下进行，他在1999年发现了sirtuins和衰老之间的联系，并在第二年首次报道了其新的催化活性。瓜伦特实验室逐渐将研究重点从对低等生物寿命的研究转向sirtuin蛋白在神经退行性疾病、癌症和其他衰老疾病中的作用。申请人是医学博士。她在临床病理学方面获得了委员会认证，并承诺在她的职业生涯中至少花费80%的时间作为研究人员。她目前在布里格姆妇女医院（BWH）担任讲师，并在麻省理工学院担任博士后。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转化研究，研究衰老的神经退行性疾病。预计该项目将为ALS的新诊断和治疗策略提供重要见解，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.