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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这项研究的作用是了解调节生物学途径和染色质功能（表观遗传学）的可逆蛋白质乙酰化反应如何与代谢网络相关联。我们专注于阐明Sir 2家族的蛋白质/组蛋白脱乙酰基酶（sirtuins）执行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、脂肪酸代谢和转录调控有关。虽然相当多的遗传学证据表明，sirtuins是主要的调节代谢途径和转录的表观遗传控制，不同的表型的分子和生化基础仍然难以捉摸。Sirtuins是NAD+依赖性蛋白质脱乙酰酶，并且是III类组蛋白脱乙酰酶（HDAC）的创始成员。需要NAD+，能量稳态中的必需中间代谢物，以及形成不寻常的产物O-乙酰基-ADP-核糖是这类蛋白质脱乙酰酶所特有的特征。这种反应的不寻常性质和众多的生物学意义导致了sirtuins作为能量代谢的中央调节的拟议模型。 我们正在利用Sirtuin KO动物以及饮食限制的动物来测量代谢变化，使用无偏见的代谢组学，以确定通过状态的代谢网络的变化？现有技术的2D-NMR和质谱方法。 这将与乙酰蛋白质组中由沉默调节蛋白酶介导的鉴定和定量变化相吻合。 这是Markley和Denu实验室之间正在进行的一项高度合作的研究。 这种collorbaration已经从NMRFAM中生成了先前的数据集，这些数据集具有出色的发现和对该项目关键的代谢差异的识别。 这项研究由威斯康星州合作基金资助。