SIRTUIN PROTEIN-HISTON DEACETYLASE STUDY

Sirtuin 蛋白-组蛋白去乙酰化酶研究

• 批准号: 7954658
• 负责人: JOHN M DENU
• 金额: $ 0.15万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954658
• 关键词: Animals; Apoptosis; Arts; Biochemical; Biochemical Pathway; Biological; Biological Process; Chromatin; Computer Retrieval of Information on Scientific Projects Database; Data Set; Deacetylase; Energy Metabolism; Enzymes; Epigenetic Process; Funding; Genetic; Genetic Transcription; Grant; Histones; Homeostasis; Institution; Link; Longevity; Measures; Mediating; Metabolic; Metabolic Pathway; Modeling; Molecular; Nature; Neurons; O-Acetyl-ADP-Ribose; Organism; Pathway interactions; Phenotype; Protein Acetylation; Protein Family; Proteins; Reaction; Regulation; Research; Research Personnel; Resources; Role; Sir2-like Deacetylases; Sirtuins; Source; Transcriptional Regulation; United States National Institutes of Health; Wisconsin; base; blood glucose regulation; fatty acid metabolism; member; metabolomics

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The role of this study is to understand how reversible protein acetylation reactions that regulate biological pathways and chromatin function (epigenetics), are linked to metabolic networks. We are focused on elucidating the mechanisms by which the Sir2 family of protein/histone deacetylases (sirtuins), perform their biological functions. Sirtuins have been implicated in organism longevity, neuronal protection, glucose homeostasis, apoptosis, fatty-acid metabolism and transcriptional control. Although considerable genetic evidence suggests that sirtuins are master regulators of metabolic pathways and epigenetic control of transcription, the molecular and biochemical basis for the varied phenotypes has remained elusive. Sirtuins are NAD+-dependent protein deacetylases and founding members of the class III histone deacetylases (HDACs). The requirement for NAD+, an essential intermediary metabolite in energy homeostasis, and the formation of an unusual product O-acetyl-ADP-ribose are features unique to this class of protein deacetylases. The unusual nature of this reaction and the numerous biological implications have led to the proposed model of sirtuins as central regulations of energy metabolism. We are utilizing Sirtuin KO animals as well as dietary restricted animals to measure the metabolic changes using an unbiased metabolomics to identify changes to metabolic networks through state-of?the art 2D-NMR and mass spectral approaches. This will dovetail with the identification and quantification changes in the acetylproteome as mediated by sirtuin enzymes. This is a highly collaborative study that has been ongoing between the Markley and Denu Lab. This collorbaration has generated previous data sets from the NMRFAM with excellent findings and identification of metabolic differences key to the project. This study is funded by Wisconsin Partnership Fund.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 这项研究的作用是了解调节生物途径和染色质功能（表观遗传学）的可逆蛋白质乙酰化反应如何与代谢网络联系起来。我们致力于阐明蛋白质/组蛋白脱乙酰酶 Sir2 家族（sirtuins）发挥其生物学功能的机制。 Sirtuins 与生物体寿命、神经元保护、葡萄糖稳态、细胞凋亡、脂肪酸代谢和转录控制有关。尽管大量遗传证据表明去乙酰化酶是代谢途径和转录表观遗传控制的主要调节因子，但不同表型的分子和生化基础仍然难以捉摸。 Sirtuins 是 NAD+ 依赖性蛋白脱乙酰酶，也是 III 类组蛋白脱乙酰酶 (HDAC) 的创始成员。对 NAD+（能量稳态中必需的中间代谢物）的需求以及不寻常产物 O-乙酰基-ADP-核糖的形成是此类蛋白质脱乙酰酶的独特特征。这种反应的不寻常性质和众多的生物学意义导致了sirtuins模型被提出作为能量代谢的中心调节。 我们利用 Sirtuin KO 动物以及饮食受限的动物来测量代谢变化，使用无偏代谢组学通过最先进的 2D-NMR 和质谱方法来识别代谢网络的变化。 这将与沉默调节蛋白酶介导的乙酰蛋白质组的鉴定和定量变化相吻合。 这是马克利和德努实验室之间正在进行的一项高度合作的研究。 这种合作已经从 NMRFAM 生成了先前的数据集，并具有对该项目至关重要的代谢差异的出色发现和识别。 这项研究由威斯康星州合作基金资助。