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: 8442941
• 负责人: Stephen J. Lippard
• 金额: $ 36.11万
• 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/8442941
• 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.

描述（由申请人提供）：本研究的长期目标是设计用于结合、可视化和定量神经生物学系统中移动的锌的分子传感器。大脑海马神经元突触前囊泡中储存的内源性锌在生理刺激时释放，在学习和记忆中发挥不完全定义的作用。类似的移动的锌储存存在于嗅球（OB）中，以更直接的信号传导途径处理从鼻子传递的气味信息。大脑中不受控制的Zn 2+释放与癫痫发作、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Zn 2+响应传感器，其可以跟踪响应于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、评估和优化是本研究项目的主要组成部分。每个传感器最多有三个模块。最低限度，将有锌结合和锌报告单位。结合模块通常包含具有可变Zn2+亲和力、对Zn2+在神经元组织中的竞争离子的选择性以及快速可逆配位以监测ms时间尺度上的生物学变化的多齿配体。锌报告模块将是荧光或磷光的，用于光学成像（OI）实验，或能够改变水弛豫速率，用于磁共振成像（MRI）研究。荧光报告物包括吨酮和单壁碳纳米管衍生物。磷光传感器基于环化铱（III）络合物。MRI构建体利用锰（III）卟啉。通过附加一个可选的第三模块的策略，以本地化基于光致发光的锌传感器编程的细胞目标，以调查Zn2+的动力学在特定位点的信号转导途径后的生理或病理刺激。一个相关的目标是制备锌选择性，快速螯合剂，用于结合移动的Zn 2+的生物功能的研究。锌传感器和螯合剂的热力学、动力学、物理学和理论研究将指导合成方向以进行改进以优化其在应用中的效用。具体的应用包括OI的假设有关的作用，移动的锌在苔藓纤维突触在海马和肾小球在OB和可视化的生理和病理条件下的海马移动的锌活动的MRI的神经传递的评价。该项目与公共卫生有关，因为它将提供测试有关大脑中移动的Zn 2+功能的理论的手段，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）和更急性毒性脑病的假定关联的手段。所设计的化学也将促进工具的开发，以测量发生在其他组织如前列腺和胰腺中的移动的锌储存，其中移动的Zn 2+的定量具有早期检测涉及这些器官的疾病的潜力。