Investigation of Zinc Neurochemistry by Optical Sensing and MRI

通过光学传感和 MRI 研究锌神经化学

• 批准号: 8053872
• 负责人: Stephen J. Lippard
• 金额: $ 37.42万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053872
• 关键词: Acute; Address; Adopted; Affinity; Alzheimer' s Disease; Antibodies; Binding; Biological; Biological Monitoring; Biological Process; Brain; Cell Culture Techniques; Cell surface; Cells; Chelating Agents; Chemicals; Chemistry; Complex; Craniocerebral Trauma; Detection; Diagnostic; Disease; Early Diagnosis; Evaluation; Extracellular Protein; Face; Fluorescein; Genetic Programming; Goals; Grant; Hippocampal Mossy Fibers; Hippocampus (Brain); Homeostasis; Hybrids; Imagery; Imaging Device; In Vitro; Intercept; Investigation; Ions; Iridium; Ischemia; Kinetics; Learning; Ligands; Liquid substance; Long-Term Potentiation; Magnetic Resonance Imaging; Manganese; Measures; Membrane; Memory; Metals; Microscopic; Molecular; Nanotubes; Neurobiology; Neurodegenerative Disorders; Neurons; Neurosciences; Nose; Oligonucleotides; Optics; Organ; Organelles; Pancreas; Pathway interactions; Penetration; Peptides; Physiological; Polymers; Porphyrins; Positioning Attribute; Presynaptic Terminals; Process; Property; Prostate; Proteins; Protons; Public Health; Relaxation; Reporter; Reporting; Research; Research Project Grants; Rhodamine; Role; Sampling; Seizures; Seminal; Series; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Solutions; Stimulus; Synapses; Synaptic Vesicles; Synthesis Chemistry; System; Testing; Theoretical Studies; Thermodynamics; Time; Tissues; Toxic Encephalopathy; Vesicle; Water; Work; Zinc; absorption; analog; base; cellular targeting; density; dentate gyrus; design; improved; in vivo; mossy fiber; neurochemistry; neurotransmission; olfactory bulb; optical imaging; phosphorescence; presynaptic; programs; protein aminoacid sequence; public health relevance; quantum; ratiometric; research study; response; sensor; single walled carbon nanotube; theories; tool; tool development

DESCRIPTION (provided by applicant): The long-term goal of this research is to devise molecular sensors for binding, visualizing, and quantifying mobile zinc in neurobiological systems. Endogenous stores of zinc in presynaptic vesicles of hippocampal neurons in the brain are released upon physiological stimulation to perform an incompletely defined role in learning and memory. Similar mobile zinc stores present in the olfactory bulb (OB) process odorant information trans- mitted from the nose in a more direct signaling pathway. Uncontrolled Zn2+ release in the brain is associated with damage following seizure, ischemia, or blunt head trauma. In order to study these neurochemical phenomena, Zn2+ responsive sensors are required that can track the spatial and temporal distribution of the mobilized ion in response to physiological and pathological stimuli. The design, synthesis, evaluation, and optimization of the sensors constitute the major components of this research project. Each sensor will have up to three modules. Minimally, there will be zinc-binding and zinc-reporting units. The binding modules typically comprise multidentate ligands with variable Zn2+ affinity, selectivity for Zn2+ over competing ions in neuronal tissue, and fast, reversible coordination to monitor biological changes on the ms time scale. The zinc-reporting module will be either fluorescent or phosphorescent, for use in optical imaging (OI) experiments, or capable of altering water relaxation rates, for use in magnetic resonance imaging (MRI) studies. Fluorescent reporters include xanthenone and single-walled carbon nanotube derivatives. Phosphorescent sensors are based on cyclometalated iridium(III) complexes. MRI constructs utilize manganese(III) porphyrins. Strategies are adopted for attaching an optional third module to localize photoluminescence-based zinc sensors to programmed cellular targets to investigate Zn2+ dynamics at specific sites in a signal transduction pathway following physiological or pathological stimulation. An associated objective is to prepare zinc-selective, rapid chelating agents to be used in conjunction with investigations of the biological functions of mobile Zn2+. Thermodynamic, kinetic, photophysical, and theoretical studies of the zinc sensors and chelators will guide synthetic directions for making improvements to optimize their utility in applications. Specific applications include the evaluation by OI of hypotheses concerning the roles of mobile zinc in neurotransmission at mossy fiber synapses in the hippocampus and at glomeruli in the OB and the visualization by MRI of mobile zinc activity in the hippocampus under physiological and pathological conditions. This project is relevant to public health, for it will provide the means to test theories about the functions of mobile Zn2+ in the brain as well as the means by which to assess the postulated association of uncontrolled zinc levels with neurodegenerative diseases, such as Alzheimer's, and with more acute toxic encephalopathies. The chemistry devised will also facilitate the development of tools to measure mobile zinc stores that occur in other tissues such as the prostate and pancreas, where quantitation of mobile Zn2+ has the potential for early detection of diseases involving these organs. PUBLIC HEALTH RELEVANCE: This research involves the synthesis, characterization, and application of optical and magnetic resonance imaging tools to investigate the underlying mechanisms of mobile zinc in the brain. Signal transduction by mobile zinc is implicated in learning and memory and in the processing of odorant information from the nose. Uncontrolled zinc levels contribute to neurodegenerative diseases, which may be responsive to zinc-selective chelating agents also devised in the project.

描述（由申请人提供）：本研究的长期目标是设计用于结合、可视化和量化神经生物系统中移动锌的分子传感器。大脑海马神经元突触前囊泡中的内源性锌储存在生理刺激下被释放，在学习和记忆中发挥不完全确定的作用。嗅球（OB）中存在类似的移动锌库，以更直接的信号通路处理从鼻子传输的气味信息。大脑中不受控制的 Zn2+ 释放与癫痫、缺血或钝性头部创伤后的损伤有关。为了研究这些神经化学现象，需要 Zn2+ 响应传感器来跟踪响应生理和病理刺激的动员离子的空间和时间分布。传感器的设计、合成、评估和优化构成了该研究项目的主要组成部分。每个传感器最多具有三个模块。至少会有锌结合单元和锌报告单元。结合模块通常包含具有可变 Zn2+ 亲和力的多齿配体，对神经组织中 Zn2+ 相对于竞争离子的选择性，以及快速、可逆的协调以监测毫秒时间尺度的生物变化。锌报告模块可以是荧光或磷光的，用于光学成像（OI）实验，或者能够改变水弛豫率，用于磁共振成像（MRI）研究。荧光报道分子包括呫吨酮和单壁碳纳米管衍生物。磷光传感器基于环金属化铱(III) 络合物。 MRI 构造利用锰 (III) 卟啉。采用附加可选的第三个模块的策略，将基于光致发光的锌传感器定位到编程的细胞目标，以研究生理或病理刺激后信号转导途径中特定位点的 Zn2+ 动态。一个相关的目标是制备锌选择性快速螯合剂，用于与移动 Zn2+ 的生物功能研究结合使用。锌传感器和螯合剂的热力学、动力学、光物理和理论研究将指导合成方向，以优化其在应用中的效用。具体应用包括通过 OI 评估关于移动锌在海马苔藓纤维突触和 OB 肾小球神经传递中的作用的假设，以及通过 MRI 可视化生理和病理条件下海马移动锌活性。该项目与公共卫生相关，因为它将提供测试有关大脑中移动锌离子功能的理论的方法，以及评估不受控制的锌水平与神经退行性疾病（如阿尔茨海默氏症）和更急性中毒性脑病之间假定关联的方法。所设计的化学方法还将促进工具的开发，以测量前列腺和胰腺等其他组织中存在的移动锌储存，其中移动锌2+的定量有可能早期检测涉及这些器官的疾病。 公共健康相关性：这项研究涉及光学和磁共振成像工具的合成、表征和应用，以研究大脑中移动锌的潜在机制。移动锌的信号转导与学习和记忆以及来自鼻子的气味信息的处理有关。不受控制的锌水平会导致神经退行性疾病，这可能对该项目中设计的锌选择性螯合剂有反应。