The role of Sirt1 in Huntington's Disease.

Sirt1 在亨廷顿病中的作用。

• 批准号: 8392710
• 负责人: DIMITRI KRAINC
• 金额: $ 36.82万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392710
• 关键词: Acetylation; Affect; Alzheimer' s disease model; Amyotrophic Lateral Sclerosis; Antibodies; Atrophic; Autophagocytosis; Brain; Brain-Derived Neurotrophic Factor; CREB1 gene; Cellular Stress; Complex; Corpus striatum structure; Data; Deacetylase; Deacetylation; Dependence; Disease Progression; Disease model; Dose; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Goals; HSF1; Heat-Shock Response; Huntington Disease; In Vitro; Knock-out; Life; Light; Link; Lysine; Mediating; Metabolic; Mitochondria; Molecular Profiling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Physiological; Play; Principal Investigator; Process; Proteins; Regulation; Research Project Grants; Resistance; Role; Sirtuins; Staging; Stress; System; Testing; Testis; Transcriptional Regulation; Transducers; Transgenic Mice; Validation; Wallerian Degeneration; Wild Type Mouse; Work; aging brain; base; drug development; human Huntingtin protein; in vivo; mouse model; mutant; neuroprotection; overexpression; pre-clinical; programs; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Sirt1, an NAD-dependent protein deacetylase has emerged as important regulator of mammalian transcription in response to cellular metabolic status and stress. SIRT1 protects from Wallerian degeneration and protects against neurodegeneration in models of Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's and Parkinson's disease. The fact that Sirt1 protects in various disease models suggests a more general function of Sirt1 in normal and abnormal neuronal function. However, normal function of Sirt1 in neurons remains largely unknown. As part of our initial effort to defin the physiological function of Sirt1 in CNS, we found that SIRT1 deacetylates TORC1 (Transducer of Regulated CREB activity) and activates CREB mediated transcription. As coactivator of CREB, TORC1 regulates transcription of a number of important genes that have been implicated in the pathogenesis of neurodegenerative disorders, such as PGC-1alpha and BDNF. TORC1 regulates neuronal activity-dependent CREB transcription and we hypothesize that Sirt1 plays a role in this process. Since TORC1 is only expressed in CNS and testis, it potentially represents a unique target of neuronal Sirt1 function. However, it is likely that Sirt1 regulates other targets in neurons, especially in light of the fact that more than forty targets of Sirt1 have been identified in non-neuronal systems. We found that Sirt1 deactylase activity was inhibited by mutant huntingtin. This inhibition presumably leads to deregulation of numerous targets of Sirt1 in HD brain. We propose to examine the role of Sirt1 and its targets in normal and HD neurons. Neuronal activity-dependent regulation gene expression will be assessed in primary neurons in the presence or absence of Sirt1. TORC1-dependent expression profiles will be compared with Sirt1 profiles. We will also examine if higher levels of Sirt1 overexpression afford dose-dependent neuroprotection in HD-like mice. Unbiased and biased studies will be performed to examine Sirt1 targets in HD pathogenesis. More generally, this work will further our understanding of the precise mechanistic link between the sirtuins and healthy brain aging, and potentiate development of drugs that delay and ameliorate neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: We propose a research project to accelerate the pre-clinical validation of sirtuins as therapeutic targets for HD. These studies will also examine Sirt1-mediated regulation of transcriptional networks in normal and diseased brain. If successful, this approach will have high impact for HD as well as other neurodegenerative disorders.

描述（由申请人提供）：Sirt1是一种NAD依赖性蛋白脱乙酰酶，已成为哺乳动物转录的重要调节因子，以响应细胞代谢状态和应激。SIRT 1在阿尔茨海默病、肌萎缩侧索硬化、亨廷顿病和帕金森病模型中保护免受沃勒变性和神经变性。Sirt1在各种疾病模型中保护的事实表明Sirt1在正常和异常神经元功能中具有更普遍的功能。然而，Sirt1在神经元中的正常功能在很大程度上仍然未知。作为我们最初确定Sirt 1在CNS中的生理功能的努力的一部分，我们发现SIRT 1使TORC 1（调节CREB活性的转导子）脱乙酰并激活CREB介导的转录。作为CREB的共激活因子，TORC 1调节许多重要基因的转录，这些基因与神经退行性疾病的发病机制有关，如PGC-1 α和BDNF。TORC1调节神经元活性依赖性CREB转录，我们假设Sirt1在这一过程中发挥作用。由于TORC 1仅在CNS和睾丸中表达，因此它可能代表神经元Sirt 1功能的独特靶标。然而，Sirt 1很可能 调节神经元中的其他靶点，特别是考虑到神经元中有40多个靶点， Sirt1已在非神经系统中被鉴定。我们发现Sirt1脱乙酰酶活性被突变的亨廷顿蛋白抑制。这种抑制可能导致HD脑中Sirt1的许多靶点失调。我们建议研究Sirt1及其靶标在正常和HD神经元中的作用。将在存在或不存在Sirt1的情况下在原代神经元中评估神经元活性依赖性调节基因表达。将TORC1依赖性表达谱与Sirt1谱进行比较。我们还将研究更高水平的Sirt1过表达是否在HD样小鼠中提供剂量依赖性神经保护。将进行无偏倚和偏倚研究，以检查HD发病机制中的Sirt1靶点。更一般地说，这项工作将进一步加深我们对sirtuins和健康大脑衰老之间精确机制联系的理解，并加强延迟和改善神经退行性疾病药物的开发。 公共卫生相关性：我们提出了一个研究项目，以加速sirtuins作为HD治疗靶点的临床前验证。这些研究还将研究Sirt1介导的正常和患病大脑中转录网络的调节。如果成功，这种方法将对HD以及其他神经退行性疾病产生很大影响。