NMR Technologies for Integrating Structure, Function and Disease

整合结构、功能和疾病的 NMR 技术

• 批准号: 10323282
• 负责人: Katherine Anne Henzler-Wildman
• 金额: $ 119.26万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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/10323282
• 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

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赠款于2019年5月提交，然后Alexander Barnes教授搬到Eth-Zurich和教授之前。 乍得·林斯特拉（Chad Rienstra）被招募到西澳大学麦迪逊（UW-Madison）。现在，Rienstra是UW-Madison的正式教授 谈判了NMRFAM的固态NMR（SSNMR）计划的重大投资（新和/或搬家 来自伊利诺伊州），包括三个屏蔽的600 MHz磁铁，一个750 MHz宽的钻头，四个光谱仪， 600-750 MHz的几个定制设计的魔法旋转（MAS）探针，并升级为900 MHz 光谱仪，立即对DBP6的数据收集产生了影响，其他 2020年初进行的实验。 此外，国家科学基金会中期研究基础架构2提案 高级NMR”，由UW-Madison Pis（Rienstra和Henzler-Wildman）合作提交 在U. Georgia的UConn Health和Art Edison的Jeff Hoch与乔治亚州的Art Art和Art Art一起，正在谈判后期 NSF。如果资助，该赠款将在〜2022-23中将1.1 GHz专用的SSNMR光谱仪带到NMRFAM。 这些发展激发了该A1应用程序的几个更改，更明确地强调了 NMRFAM的SSNMR程序： （1）Rienstra现在是联系PI和Henzler-Wildman Co-Pi。 （2）TR＆D1现在包括针对微型填料开发和样品操纵的子iams 利用<1 mm转子直径的超快速MAS（> 100 kHz）的最新突破的工具；这 扩大TR＆D 1的范围和影响。在梯度下，NMR的基准和基准也是 更清楚地描述了原则实验。 （3）TR＆D2现在解决了SSNMR数据收集中的关键瓶颈，强调： （a）用于参数优化和光谱仪配置的自动化； （b）新的窄孔魔法旋转探针设计，位于600-900 MHz（将适用于1.1 GHz及以后更高）；和 （c）与数据处理（TR＆D3）的实时反馈交互。 （4）TR＆D3现在利用NMRFAM软件产品和继续技术开发来实现固体 状态NMR，包括分配，结构确定，改进和验证工具，并且更多 与其他提案的其余部分清楚地集成在一起。 （5）DBPS 5、6和7已更改为包括发达和有影响力的合作 Rienstra和Paul Kotzbauer（Wash。U.Medicine，Lewy Bodies and Synucleiopathies），Marty Burke（U. 伊利诺伊州，抗真菌药物）和詹姆斯·莫里西（James Morrissey）（美国密歇根州，血液凝结）。 总体而言，该提案现在以（我们认为）更合乎逻辑/按时间顺序的方式组织 强调样品，tr＆d2光谱仪和探针，以及TR＆D3软件和分析程序。 该提案机构进一步解释了这些发展如何大大增加该项目的成本效益比率 并与当前的用户程序和NMRFAM的长期愿景集成。 这些修订还涉及A0应用程序审阅者的总体问题，包括“狭窄 tr＆d1中的范围/适度创新;“ tr＆d3”;成本效益比的弱集成；初步数据；解决方案 与TR＆D3的固体重点相比创新;上下文（解决竞争思想和先例）；和特异性 结果。最后，我们阐明了膜中不对称的前提和方法 蛋白质。