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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 这项研究的作用是了解可逆的蛋白质乙酰化反应如何与代谢网络相关。我们专注于阐明蛋白质/组蛋白脱乙酰基酶（SIRTUINS）SIR2家族执行其生物学功能的机制。 Sirtuins与生物体的寿命，神经元保护，葡萄糖稳态，凋亡，脂肪酸代谢和转录控制有关。尽管大量的遗传证据表明，Sirtuins是代谢途径的主要调节剂和转录的表观遗传控制，但各种表型的分子和生化基础仍然难以捉摸。 Sirtuins是NAD+依赖性蛋白脱乙酰基酶和III类组蛋白脱乙酰基酶（HDACS）的创始成员。 NAD+的需求是能量稳态中必不可少的中介代谢物，以及形成不寻常的产物O-乙酰基-ADP-核糖的特征是该类别的蛋白质脱乙酰基酶。这种反应的异常性质和众多的生物学意义导致提出的Sirtuins作为能量代谢的中心法规的模型。 我们利用Sirtuin KO动物以及受饮食限制的动物使用无偏代谢组学来测量代谢变化，以通过最新的2D-NMR和质谱方法来识别代谢网络的变化。 这将与Sirtuin酶介导的乙酰蛋白酶中的识别和定量变化相吻合。 这是一项高度协作的研究，在Markley和Denu实验室之间一直在进行。 该抗癌作用已从NMRFAM生成了先前的数据集，并具有出色的发现和代谢差异的识别，对项目的关键关键了。 这项研究由威斯康星州合伙基金资助。