Acquisition of a High-Field Dual Source FTICR-MS for Pharmaceutical Research

描述（由申请人提供）：本提案的目标是获得资金，用于在UW-Madison Pharmacy MS Facility中安装15 Tesla Bruker SolariX混合FTICR质谱仪。这种新仪器将提供几个独特的功能：（1）超高分辨率和高质量准确度MS，MS/MS和MSn能力;（2）多电离源;（3）增强的从头测序肽与多种碎片技术;（4）高分辨率组织成像;（5）定量基于同位素标记策略;和（6）分析小分子以及全长蛋白质的能力。这台新仪器将提供先进的MS功能，以支持28名高生产力NIH资助的研究人员的研究，其中包括49个正在进行的项目。高分辨率质谱和串联质谱的使用将有助于解决多层次的人类健康相关研究，包括：（a）了解基本生物学和疾病相关过程（涉及进食刺激的神经肽，Li博士;涉及线虫模型中信号传导的神经肽和蛋白质，斯特雷顿博士;负责维持血脑屏障的质膜蛋白质，Shusta博士;单核细胞对生物材料反应的蛋白质组学变化，Kao博士;环境毒理学反应Elfarra博士和Heideman博士;哮喘中的蛋白质信号复合物，Malter博士;视觉系统中的蛋白质-蛋白质相互作用Ruoho博士;蛋白质折叠和生物合成，Cavagnero博士;前列腺发育，干细胞维持和肿瘤生长，Peterson博士，Bushman博士和Marker博士;肢体发育中的信号事件，Sun博士;脂质及其在睡眠调节中的作用，Yin博士），（B）生物标志物的发现（神经退行性疾病，Messing和Li博士;智力迟钝小鼠模型中大脑蛋白质组的差异，Malter博士;与神经元保护相关的星形胶质细胞分泌体的变化，约翰逊博士），（c）疾病过程中蛋白质的翻译后修饰图谱（与阿尔茨海默病有关的修饰，墨菲和王博士;乳腺癌，徐博士;白血病，Collier博士），（d）发现/开发新的天然产物药物（验证天然产物全合成中的中间体和产物，Hsung博士;鉴定新型聚酮化合物并研究聚酮化合物合成的酶促机制，Shen博士;糖基化药物的结构表征，Thorson博士;新天然产物的结构阐明，Bugni博士），（e）药物递送的改进（表征用于药物递送的新型生物聚合物，Kwon博士;用于麻醉剂递送的新含氟化合物的表征，Mecozzi博士），以及（f）临床药物分析（麻醉剂药理学特征评价，皮尔斯博士;临床样本药物代谢研究，Kolesar、Bailey和Wilding博士）。这一系列广泛的项目的进展将通过用户组之间的密切合作，李博士，一个具有超过17年的生物质谱经验的高生产力的教员，和斯嘉丽博士，威斯康星大学麦迪逊分校药理学-MS设施主任的有效使用新仪器催化。 公共卫生相关性：成功收购高分辨率布鲁克SolariX Hybrid FTICR质谱仪将对威斯康星大学麦迪逊分校（UWM）健康科学校区开展的一系列生物医学研究项目产生重大而广泛的影响。这种尖端仪器将提供先进的质谱能力，有助于破译广泛的生物过程以及疾病进展、诊断和治疗所涉及的分子细节。这种仪器增强将支持30个主要和次要用户与49资助联邦赠款或合同，并将加快正在进行的研究在13个部门或部门内的五个学院或学校和两个中心在UWM的步伐，以及提供给更广泛的科学界在麦迪逊和威斯康星州的状态。

DESCRIPTION (provided by applicant): The goal of this proposal is to obtain funding for a 15 Tesla Bruker SolariX hybrid FTICR mass spectrometer to be housed in the UW-Madison Pharmacy MS Facility. This new instrument will offer several unique features: (1) Ultra-high resolution and high mass accuracy MS, MS/MS, and MSn capabilities; (2) Multiple ionization sources; (3) Enhanced de novo sequencing of peptides with multiple fragmentation techniques; (4) High resolution tissue imaging; (5) Quantitation based on isotopic labeling strategies; and (6) Ability to analyze small molecules as well as full-length proteins. This new instrument will provide advanced MS capabilities to support the research of 28 highly productive NIH-funded investigators with 49 ongoing projects. The use of high resolution MS and tandem MS will help to address multiple levels of human health-related research including, (a) understanding of fundamental biological and disease related processes (neuropeptides involved in feeding stimuli, Dr. Li; neuropeptides and proteins involved in signaling in a nematode model, Dr. Stretton; plasma membrane proteins responsible for maintenance of the blood-brain barrier, Dr. Shusta; proteomic changes in monocytes in response to biomaterials, Dr. Kao; environmental toxicological responses Drs. Elfarra, and Heideman; protein signaling complexes in asthma, Dr. Malter; protein-protein interactions in the visual system Dr. Ruoho; protein folding and biosynthesis, Dr. Cavagnero; prostate development, stem cell maintenance and tumor growth, Drs. Peterson, Bushman and Marker; signaling events in limb development, Dr. Sun; lipids and their role in sleep regulation, Dr. Yin), (b) discovery of biomarkers (for neurodegenerative diseases, Drs. Messing and Li; differences in the brain proteome in mouse models of mental retardation, Dr. Malter; changes in astrocyte secretome associated with neuronal protection, Dr. Johnson), (c) posttranslational modification mapping of proteins in disease process (modifications involved in Alzheimer's disease, Drs. Murphy and Wang; breast cancer, Dr. Xu; leukemia, Dr. Collier), (d) discovery/development of novel natural product pharmaceuticals (validate intermediates and products in the total synthesis of natural products, Dr. Hsung; identify novel polyketides and investigate enzymatic mechanisms of polyketide synthesis, Dr. Shen; structural characterization of glycorandomized pharmaceuticals, Dr. Thorson; structural elucidation of new natural products, Dr. Bugni), (e) improvement of drug delivery (characterization of novel biopolymers for drug delivery, Dr. Kwon; characterization of new fluorine-containing compounds for delivery of anesthetics, Dr. Mecozzi), and (f) clinical pharmaceutical analysis (evaluation of pharmacological profiles of anesthetics, Dr. Pearce; investigation of drug metabolism in clinical samples, Drs. Kolesar, Bailey, and Wilding). Progress on this broad array of projects will be catalyzed by the effective usage of the new instrument through close cooperation among the user groups, Dr. Li, a highly productive faculty member with more than 17 years of experience in biological mass spectrometry, and Dr. Scarlett, the UW-Madison Pharmacy-MS Facility Director. PUBLIC HEALTH RELEVANCE: Successful acquisition of a high resolution Bruker SolariX Hybrid FTICR mass spectrometer will have significant and broad impact on a wide array of biomedical research projects conducted on the health sciences campus at the University of Wisconsin-Madison (UWM). This cutting-edge instrument will provide advanced mass spectrometric capabilities that facilitate deciphering molecular details involved in a broad spectrum of biological processes as well as disease progression, diagnosis and treatment. This instrumentation enhancement will support 30 major and minor users with 49 funded federal grants or contracts, and will accelerate the pace of ongoing research in 13 departments or divisions within five colleges or schools and two centers at UWM as well as being available to the broader scientific community in Madison and the State of Wisconsin.