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-晶格弛豫速率常数的磁场依赖性，也称为磁弛豫色散（MRD），报告了分子内和分子间运动产生的波动的功率密度，作为核拉莫尔频率的函数，其可以在5 kHz至500 MHz范围内变化（1 H）。使用顺磁贡献的核弛豫的有效频率范围扩展到0.3太赫兹或时间尺度的顺序为1 ps。结合适当的统计理论，MRD配置文件提供了一个强大的方法，用于研究分子动力学，特别是蛋白质动力学，以及修改核自旋弛豫的因素，如在MRI中使用的弛豫剂。该实验室已组装了用于MRD测量的独特仪器。我们建议：基于来自旋转固定蛋白质的MRD数据，表征蛋白质中内部捕获的水分子的动力学;定义膜结合蛋白质在膜模型系统中控制水自旋-晶格弛豫中的作用;将自旋-分形子弛豫理论扩展到四极自旋、氘和氮-14的情况，以测试该理论的通用性和对蛋白质中能量再分布的影响;测量邻近蛋白质中特定顺磁中心的水的高频运动;定义与旋转固定蛋白质缀合的金属螯合物和有机基团的最大水质子弛豫率的条件，这对于理解靶向MRI造影剂如何起作用很重要;从10 kHz到500 MHz测量切除组织系统的精确弛豫色散曲线，以提供完整的数据集，用于与临床环境中积累的更分散的实验进行比较;测量模型组织基质中通常观察到的代谢物的31 P和13 C MRD谱，以提供对宽场范围内的弛豫机制的理解;测量MRD谱，并测试作为模型刚性线性系统的DNA的自旋-分形子弛豫理论;使用蛋白质自旋的直接检测来测量蛋白质中特定分子内载体的MRD谱;并使用碳酸酐酶II和突触结合蛋白I的C2 A结构域中的锌和钙金属位点与氮氧标记的半胱氨酸突变体组合来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关系到我们如何理解蛋白质中的能量再分配，或者结构扰动如何通过结构传播作为功能的可能组成部分。这项工作在临床磁成像的背景下，无论是在提取额外的信息，从现有的方法和开发新的类别的靶向造影剂的直接应用。 该项目将使用核自旋-晶格弛豫速率常数的测量来推断影响MRI对比度的蛋白质分子内和分子间运动的性质，以及可能从体内磁共振协议中获得的信息。包括针对MRI的自旋弛豫或造影剂的研究，其在设计和作用上与目前使用的可溶性造影剂有根本不同。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是重要的。