SIRTUIN PROTEIN-HISTON DEACETYLASE STUDY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项研究的作用是了解调节生物途径和染色质功能的可逆蛋白质乙酰化反应(表观遗传学)是如何与代谢网络联系起来的。我们致力于阐明Sir2蛋白/组蛋白脱乙酰酶(Sirtuins)家族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、脂肪酸代谢和转录调控有关。虽然大量的遗传证据表明sirtuins是代谢途径和转录的表观遗传控制的主要调节者，但不同表型的分子和生化基础仍然难以捉摸。Sirtuins是依赖NAD+的蛋白去乙酰基酶，也是组蛋白脱乙酰基酶(HDAC)的创始成员。对NAD+的需求，一种能量平衡的重要中间代谢产物，以及一种不寻常的产物O-乙酰-ADP-核糖的形成是这类蛋白脱乙酰基酶所独有的特征。这种反应的不同寻常的性质和众多的生物学意义导致了提出的sirtuins模型作为能量代谢的中心调节。我们正在利用Sirtuin KO动物以及饮食受限的动物来测量代谢变化，使用无偏见的代谢组学，通过最先进的2D-核磁共振和质谱学方法来识别代谢网络的变化。这将与sirtuin酶介导的乙酰蛋白质组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。这种整理已经从NMRFAM生成了以前的数据集，这些数据集具有出色的发现和对该项目至关重要的代谢差异的识别。这项研究是由威斯康星州伙伴基金资助的。

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.