NMR Technologies for Integrating Structure, Function and Disease

整合结构、功能和疾病的 NMR 技术

基本信息

批准号：
10089598
负责人：
Katherine Anne Henzler-Wildman
金额：
$ 191.65万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-02 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10089598
关键词：
3D Print Address Algorithms Amyloid Amyloid Fibrils Antifungal Agents Area Arts Automatic Data Processing Automation Automobile Driving Benchmarking Binding Biological Biology Biomedical Research Biomolecular Nuclear Magnetic Resonance Biotechnology Blood coagulation Caliber Calibration Chad Chemicals Chronology Collaborations Communities Complex Computer software Costs and Benefits Custom Data Data Analyses Data Collection Development Disease Educational workshop Ensure Environment Enzymes Feedback Foundations Free Energy Funding Future G-Protein-Coupled Receptors Goals Grant Health Human Resources Illinois In Vitro Instruction Investments Ionic Strengths Kinetics Knowledge Learning Lewy Bodies Ligands Linux Magic Measurement Mediation Medicine Membrane Membrane Proteins Methods Michigan Microscopic Modeling Modernization Multienzyme Complexes Neurodegenerative Disorders Nucleic Acids Operating System Outcome Pathogenicity Pathology Pharmaceutical Preparations Physiological Preparation Procedures Proteins Protocols documentation Publishing Reporting Reproducibility Research Infrastructure Resolution Resources Rest Running Sampling Science Services Solid Specificity Spectrum Analysis Speed Sterols Structure Surface System Technology Technology Transfer Testing Thermodynamics Time Tissue Sample Translating Ursidae Family Validation Vision base community engagement computerized data processing cost data acquisition data quality design experimental study flexibility graphical user interface improved innovation ionization constant meetings new technology programs protein folding quantum chemistry recruit senior faculty small molecule solid state solid state nuclear magnetic resonance technology development tool web site

项目摘要

INTRODUCTION TO REVISED APPLICATION The A0 grant was submitted in May 2019, before Prof. Alexander Barnes moved to ETH-Zurich and before Prof. Chad Rienstra was recruited to UW-Madison. Now Rienstra is officially a Full Professor at UW-Madison, after having negotiated major investments in the solid-state NMR (SSNMR) program at NMRFAM (new and/or moving from Illinois) including three shielded 600 MHz magnets, one 750 MHz wide bore magnet, four spectrometers, several custom-designed magic-angle spinning (MAS) probes at 600-750 MHz, and upgrades to the 900 MHz spectrometer, which immediately have had an impact on data collection for DBP6 in late 2019 and for other experiments in progress during early 2020. Furthermore, the National Science Foundation Mid-Scale Research Infrastructure-2 proposal on "Network for Advanced NMR", which was submitted by UW-Madison PIs (Rienstra and Henzler-Wildman) in collaboration with Jeff Hoch at UConn Health and Art Edison at U. Georgia, is in late stages of negotiation and review with NSF. If funded, this grant would bring a 1.1 GHz dedicated SSNMR spectrometer to NMRFAM in ~2022-23. These developments have motivated several changes to this A1 application which more explicitly emphasizes the SSNMR program at NMRFAM: (1) Rienstra is now contact PI and Henzler-Wildman co-PI. (2) TR&D1 now includes sub-aims targeting development of micro-rotor packing and sample manipulation tools to leverage recent breakthroughs in ultra-fast MAS (>100 kHz) at <1 mm rotor diameters; this broadens the scope and impact of TR&D 1. Baselines and benchmarks for NMR under gradients are also more clearly described and proof-of-principle experiments are in place. (3) TR&D2 now addresses critical bottlenecks in SSNMR data collection, emphasizing: (a) automation for parameter optimization and spectrometer configuration; (b) new narrow bore magic-angle spinning probe designs at 600-900 MHz (that will be applicable at 1.1 GHz and higher in the future); and (c) real-time feedback interaction with data processing (TR&D3). (4) TR&D3 now leverages NMRFAM software products and continuing technology development for solid- state NMR, including assignment, structure determination, refinement and validation tools, and it is more clearly integrated with the rest of the proposal. (5) DBPs 5, 6 and 7 have been changed to include well-developed and impactful collaborations between Rienstra and Paul Kotzbauer (Wash. U. Medicine, Lewy bodies and synucleiopathies), Marty Burke (U. Illinois, antifungal drugs), and James Morrissey (U. Michigan, blood coagulation). Overall the proposal is now organized in (we think) a more logical/chronological manner, with TR&D1 emphasizing samples, TR&D2 the spectrometer and probes, and TR&D3 the software and analysis procedures. The proposal body further explains how these developments greatly augment the cost-benefit ratio for the project and integrate with the current user program and the long-term vision of NMRFAM. The revisions also address the overarching concerns of reviewers of the A0 application including "narrow scope/modest innovation in TR&D1"; "weak integration of TR&D3"; cost-benefit ratio; preliminary data; solution vs. solids emphasis of TR&D3; innovation; context (addressing competing ideas and precedents); and specificity of outcomes. Finally, we have clarified the premise and approach with respect to asymmetry in membrane proteins.

修订申请简介 A0 资助是在 2019 年 5 月提交的，当时 Alexander Barnes 教授搬到了苏黎世联邦理工学院，在 Alexander Barnes 教授之前。查德·里恩斯特拉 (Chad Rienstra) 被招入威斯康星大学麦迪逊分校。现在，Rienstra 正式成为威斯康辛大学麦迪逊分校的正教授，之后已就 NMRFAM 的固态 NMR (SSNMR) 项目的重大投资进行了谈判（新的和/或移动的）来自伊利诺伊州）包括三个屏蔽 600 MHz 磁体、一个 750 MHz 宽孔磁体、四个光谱仪、多个定制设计的魔角旋转 (MAS) 探头，频率为 600-750 MHz，并升级到 900 MHz 光谱仪，这立即对 2019 年底 DBP6 和其他数据收集产生了影响 2020 年初正在进行的实验。此外，国家科学基金会中型研究基础设施-2关于“Network for Advanced NMR”，由威斯康星大学麦迪逊分校 PI（Rienstra 和 Henzler-Wildman）合作提交与康涅狄格大学健康中心的 Jeff Hoch 和美国佐治亚州的 Art Edison 合作，目前正处于与美国国家科学基金会。如果获得资助，这笔赠款将在 2022-23 年间为 NMRFAM 带来一台 1.1 GHz 专用 SSNMR 波谱仪。这些发展促使 A1 应用程序发生了一些变化，更明确地强调 NMRFAM 的 SSNMR 程序： (1) Rienstra 现在是联络 PI 和 Henzler-Wildman 联合 PI。 (2) TR&D1 现在包括针对微转子填料和样品操作开发的子目标利用转子直径 <1 mm 的超快 MAS (>100 kHz) 的最新突破的工具；这扩大了 TR&D 1 的范围和影响。梯度下 NMR 的基线和基准也已更清晰的描述和原理验证实验已经到位。 (3) TR&D2 现在解决了 SSNMR 数据收集中的关键瓶颈，强调： (a) 参数优化和光谱仪配置自动化； (b) 600-900 MHz 的新型窄孔魔角旋转探头设计（适用于 1.1 GHz 及未来更高）；和 (c) 与数据处理的实时反馈交互（TR&D3）。 (4) TR&D3 现在利用 NMRFAM 软件产品和持续的技术开发来实现固体状态NMR，包括分配、结构确定、精炼和验证工具，而且它更多与提案的其余部分明确结合。 (5) DBP 5、6 和 7 已进行更改，以包括 DBP 之间发展良好且有影响力的合作 Rienstra 和 Paul Kotzbauer（华盛顿大学医学、路易体和突触核蛋白病）、Marty Burke（华盛顿大学医学）伊利诺伊州，抗真菌药物）和 James Morrissey（美国密歇根州，凝血）。总体而言，该提案现在以（我们认为）更符合逻辑/时间顺序的方式组织，其中 TR&D1 强调样品，TR&D2 光谱仪和探头，TR&D3 软件和分析程序。提案正文进一步解释了这些发展如何极大地提高了项目的成本效益比并与NMRFAM当前的用户计划和长期愿景相结合。这些修订还解决了 A0 申请审核人员的首要关切，包括“狭隘” TR&D1 的范围/适度创新”；“TR&D3 的弱整合”；成本效益比；初步数据；解决方案与 TR&D3 的固体重点对比；创新;背景（解决相互竞争的想法和先例）；和特异性结果。最后，我们阐明了膜不对称性的前提和方法蛋白质。