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

描述(由申请人提供)：这项提案的目标是获得15特斯拉布鲁克SolariX混合FTICR质谱仪的资金，该质谱仪将安装在威斯康星大学麦迪逊药房的MS设施中。这台新仪器将提供几个独特的功能：(1)超高分辨率和高质量精度的MS、MS/MS和MSN功能；(2)多电离源；(3)利用多种碎片技术增强的多肽从头测序；(4)高分辨率组织成像；(5)基于同位素标记策略的定量；以及(6)分析小分子和全长蛋白质的能力。这一新仪器将提供先进的MS功能，以支持NIH资助的28名高生产率研究人员的49个正在进行的项目的研究。高分辨率MS和串联MS的使用将有助于解决多层次的人类健康相关研究，包括：(A)了解基本的生物和疾病相关过程(参与摄食刺激的神经肽，李博士；线虫模型中参与信号传递的神经肽和蛋白质，Stretton博士；负责维持血脑屏障的质膜蛋白，Shusta博士；单核细胞对生物材料的响应的蛋白质组变化，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体，Malter博士；视觉系统中的蛋白质-蛋白质相互作用，Rooho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和Marker博士；(C)肢体发育中的信号事件，Sun博士；血脂及其在睡眠调节中的作用，Yin博士)，(B)生物标记物的发现(神经退行性疾病，Msing和Li博士；智力低下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，Johnson博士)，(C)疾病过程中蛋白质的翻译后修饰图谱(涉及阿尔茨海默病的修改，Murphy和Wang博士；乳腺癌，Xu博士；(D)发现/开发新的天然产物药物(确认天然产物总合成中的中间体和产物，Hung博士；鉴定新的多酮并研究聚酮合成的酶机制，沈博士；糖随机药物的结构特征，Thorson博士；新的天然产物的结构说明，Bugni博士)；(E)药物释放的改进(表征药物释放的新型生物聚合物的特征，Kuan博士；用于传递麻醉剂的新的含氟化合物的特征，Mecozzi博士)，以及(F)临床药物分析(评估麻醉剂的药理学特征，Pearce博士；研究临床样本中的药物代谢(Kolesar、Bailey和Wilding博士)。这一广泛项目的进展将由新仪器的有效使用推动，用户群体、在生物质谱学方面拥有17年以上经验的高生产率教职员工Li博士和威斯康星大学麦迪逊分校药房-MS设施主任Scarlett博士之间的密切合作将推动这一广泛项目的进展。 公共卫生相关性：成功收购高分辨率Bruker SolariX混合FTICR质谱仪将对威斯康星大学麦迪逊分校(UWM)健康科学校园内开展的一系列生物医学研究项目产生重大而广泛的影响。这一尖端仪器将提供先进的质谱学功能，有助于破译涉及广泛生物过程以及疾病进展、诊断和治疗的分子细节。这项仪器改进将用49笔联邦拨款或合同支持30个主要和次要用户，并将加快5所学院或学校和威斯康星州大学两个中心内13个系或部门正在进行的研究的步伐，并可供麦迪逊和威斯康星州的更广泛的科学界使用。

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.