Magnetic Relaxation Dispersion

磁弛豫色散

• 批准号: 7371418
• 负责人: Robert George Bryant
• 金额: $ 30.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371418
• 关键词: Affect; Binding Proteins; Biological Models; Calcium; Carbonic Anhydrase II; Class; Clinical; Condition; Contrast Media; Cysteine; DNA; Data; Data Set; Dependence; Detection; Deuterium; Development; Environment; Foundations; Frequencies; Image; Label; Laboratories; Life; Magnetic Resonance; Magnetic Resonance Imaging; Magnetism; Measurement; Measures; Membrane; Metals; Methods; Modeling; Molecular; Motion; Nature; Nitrogen; Nuclear; Protein Dynamics; Proteins; Protocols documentation; Protons; Range; Rate; Relaxation; Reporting; Role; Site; Structure; System; Testing; Time; Tissue Model; Tissues; Water; Work; Zinc; base; complement C2a; density; design; in vivo; instrumentation; magnetic field; membrane model; molecular dynamics; mutant; organic base; research study; synaptotagmin I; theories; vector

DESCRIPTION (provided by applicant): The magnetic field dependence of the nuclear spin-lattice relaxation rate constant, also called the magnetic relaxation dispersion (MRD), reports the power density of fluctuations created by intra- and inter-molecular motions as a function of the nuclear Larmor frequency, which may be varied from 5 kHz to 500 MHz for 1H. The use of paramagnetic contributions to the nuclear relaxation extends the effective frequency range to 0.3 THz or time scales of order 1 ps. Combined with appropriate statistical theories, the MRD profiles provide a powerful method for studying molecular dynamics, protein dynamics in particular, and factors that modify nuclear spin relaxation such as relaxation agents used in MRI. This laboratory has assembled unique instrumentation for MRD measurements. We propose to: characterize the dynamics of internally trapped water molecules in proteins based on MRD data from rotationally immobilized proteins; define the role of membrane- bound proteins in controlling water spin-lattice relaxation in membrane model systems; extend the spin-fracton relaxation theory to the case of quadrupolar spins, deuterium and nitrogen-14, to test the generality of the theory and the implications for energy redistribution in proteins; measure the high frequency motions of water adjacent to specific paramagnetic centers in proteins; define the conditions for maximum water-proton relaxivity for metal chelate and organic radicals conjugated to rotationally immobilized proteins, which is important in understanding how targeted MRI contrast agents can work; measure accurate relaxation dispersion profiles for excised tissue systems from 10 kHz to 500 MHz to provide complete data sets for comparison with much more scattered experiments accumulated in a clinical setting; measure 31P and 13C MRD profiles for commonly observed metabolites in a model tissue matrix to provide an understanding of the relaxation mechanisms over a wide field range; measure the MRD profiles and test the spin-fracton relaxation theory for DNA as a model stiff linear system; measure the MRD profiles for specific intramolecular vectors in proteins using direct detection of protein spins; and use zinc and calcium metal sites in carbonic anhydrase II and the C2A domain of synaptotagmin I in combination with nitroxide labeled cysteine mutants to measure complete MRD profiles of these specifically defined intramolecular vectors. The results of these studies have direct bearing on how we understand energy redistribution in proteins or how structural disturbances propagate through the structure as a possible component of function. There are immediate applications of this work in the context of clinical magnetic imaging, both in extracting additional information from existing approaches and the development of new classes of targeted contrast agents. This project will use measurements of nuclear spin-lattice relaxation rate constants to deduce the nature of intra and inter-molecular motions in proteins that affect contrast in MRI and the information that may be obtained from in vivo magnetic resonance protocols. Included are studies targeted spin-relaxation or contrast agents for MRI that are fundamentally different in design and action from presently used soluble contrast agents. The molecular biophysical foundations of this work are important for understanding the functional role of protein dynamics.

描述（由申请人提供）：核自旋晶格松弛速率常数的磁场依赖性（也称为磁性松弛分散体（MRD））报告说，由内部和分子间运动产生的波动的功率密度是核LARMOR频率的函数，这可能会从5 kHz到500 mHz而变化1H。顺磁性贡献对核弛豫的贡献将有效频率范围扩展到0.3 THz或1 ps阶的时间尺度。结合适当的统计理论，MRD轮廓为研究分子动力学，尤其是蛋白质动力学以及修改核自旋松弛的因素（例如MRI中使用的松弛剂）提供了一种强大的方法。该实验室已经组装了独特的仪器以进行MRD测量。我们建议：根据旋转固定蛋白的MRD数据，表征蛋白质内部捕获的水分子的动力学；定义膜结合蛋白在控制膜模型系统中水自旋晶格松弛中的作用；将自旋裂纹弛豫理论扩展到四极旋转，氘和氮-14的情况，以测试该理论的一般性及其对蛋白质能量再分配的影响。测量与蛋白质特定顺磁心相邻的水的高频运动；确定与旋转固定蛋白结合的金属螯合和有机自由基的最大水 - 原质子松弛性的条件，这对于理解靶向MRI对比剂如何起作用至关重要；测量切除的组织系统从10 kHz到500 MHz的准确放松分散曲线，以提供完整的数据集，以与在临床环境中积累的更多分散实验进行比较；在模型组织基质中通常观察到的代谢物的31p和13c MRD谱图，以了解对宽场范围内的弛豫机制的理解；测量MRD轮廓并测试DNA作为模型硬线性系统的自旋 - 弗拉克子松弛理论；使用蛋白质自旋直接检测到蛋白质中特异性分子载体的MRD谱；并在碳酸酐酶II中使用锌和钙金属位点以及突触ov剂I的C2A结构域以及氮氧化物标记的半胱氨酸突变体的结合，以测量这些特定定义的分子内载体的完整MRD谱。这些研究的结果直接取决于我们如何理解蛋白质中的能量再分布，或者结构干扰如何通过结构传播作为功能的可能组成部分。在临床磁成像的背景下，这项工作有直接的应用，既可以从现有方法中提取其他信息以及新的靶向对比剂类别的开发中。 该项目将使用核自旋晶格松弛速率常数的测量来推断蛋白质内和分子间运动的性质，这些蛋白质会影响MRI中的对比度以及可以从体内磁共振方案中获得的信息。包括研究的靶向自旋 - 浮肿或MRI的对比剂的研究，这些研究与目前使用的可溶性对比剂的设计和作用根本不同。这项工作的分子生物物理基础对于理解蛋白质动力学的功能作用很重要。