Hyperpolarized High Field NMR Facility For Metabolic Profiling Of Human Disease

描述（由申请人提供）：该NIH共享仪器请求是建立超极化核磁共振（NMR）光谱独特设施的关键组成部分，该设施为研究各种人类疾病的代谢途径和MR成像生物标志物发现提供了10,000+倍的灵敏度提高。申请资金用于该设施的核心组件：牛津仪器生物工具HyperSenseTM动态核偏振器（DNP），这是去年首次提供的新产品。该系统将与位于Mission Bay校区UCSF核磁共振实验室的两台现有的高场500 MHz垂直孔核磁共振光谱仪相结合。这两种磁铁都专门用于运行生物医学样品，它们具有互补的功能，包括高分辨率魔角旋转（HR-MAS）光谱功能，以及带有自动样品更换器的冷冻探针。UCSF核磁共振实验室和相关的研究实验室包含所有的病理、化学和分子分析设备，以制备13C标记的底物进行极化，并将代谢谱与生物标志物发现的病理、遗传和蛋白质变化联系起来。该提案将利用这些广泛的加州大学和美国国立卫生研究院资助的资源。从DNP极化获得的灵敏度前所未有的提高将使以前认为不可能用于研究人类和动物组织、生物流体以及临床前细胞和组织培养模型的核磁共振测量成为可能。灵敏度的提高也将减少对组织和细胞进行一维和二维核磁共振研究所需的时间。DNP技术与高分辨率核磁共振波谱的耦合将允许对大量超极化13C标记底物进行研究，优化其极化，并以经济有效的方式优化超极化光谱数据的获取。这个新设施不仅对于开发利用DNP技术在组织和细胞中的应用至关重要，而且对于将这些模型系统中获得的见解转化为正在进行的临床前动物和最终临床超极化13C光谱成像研究至关重要。

DESCRIPTION (provided by applicant): This NIH shared instrument request is the key component in establishing a unique facility for hyperpolarized nuclear magnetic resonance (NMR) spectroscopy that provides a dramatic 10,000+fold improvement in sensitivity for investigating metabolic pathways and MR imaging biomarker discovery for a variety of human diseases. Funds are requested for the core component of this facility: an Oxford Instruments Biotools HyperSenseTM Dynamic Nuclear Polarizer (DNP), which is a new product first offered in the last year. This system will be combined with two existing high field 500 MHz vertical bore NMR spectrometers located in the UCSF NMR lab on the Mission Bay campus. Both magnets are dedicated to running biomedical samples and they have complimentary features, including high-resolution magic angle spinning (HR-MAS) spectroscopy capabilities, and a cryoprobe with an automatic sample changer. The UCSF NMR lab and associated research laboratory contain all of the pathology, chemistry and molecular analysis equipment required to prepare 13C labeled substrates for polarization and to correlate metabolic profiles with pathologic, genetic and protein changes for biomarker discovery. This proposal will take advantage of these extensive University of California and NIH funded resources. The unprecedented increase in sensitivity obtained from DNP polarization will permit NMR measurements previously considered impossible for studying human and animal tissue, biofluids, and pre-clinical cell and tissue culture models. Increased sensitivity will also reduce the time required for performing 1-D and 2-D NMR studies of tissues and cells. The coupling of DNP technology with high resolution NMR spectroscopy will allow the investigation of numerous hyperpolarized 13C labeled substrates, optimize their polarization and optimize the acquisition of the hyperpolarized spectroscopic data in a cost effective manner. This new facility is critical for not only developing applications that take advantage of the DNP technology in tissues and cells but also for translating the insights gained in these model systems into the ongoing pre-clinical animal and eventually clinical hyperpolarized 13C spectroscopic imaging studies being conducted at UCSF. This combination of high field NMR spectrometers with a HyperSenseTM DNP polarizer will be coupled with the large number of successful NIH-funded MR imaging research programs at UCSF and will create a unique hyperpolarized MR program that will greatly advance our understanding of the metabolism for a wide variety of diseases and result in the identification of new metabolic biomarkers of disease presence, aggressiveness and therapeutic response.