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PUNQs: Photostable, Ultrafast, Nano-optode, Quantum-dots to image Na in dendrites

PUNQ：光稳定、超快、纳米光极、量子点，用于在树突中成像 Na

基本信息

批准号：
8521208
负责人：
Timothy Tordella Ruckh
金额：
$ 5.39万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8521208
关键词：
Acute Acute Disease Adolescent Alzheimer&apos s Disease Architecture Axon Binding Biochemical Biomedical Research Brain Brain Concussion Cells Charge Chemistry Chronic Disease Dendrimers Dendrites Dendritic Spines Development Diffuse Diffusion Distal Dyes Electrophysiology (science)Elements Event Exhibits Foundations Future Glucose Glutamates Goals Head Image Individual Injection of therapeutic agent Interdisciplinary Study Ions Kinesin Kinetics Knowledge Laboratories Laser Scanning Microscopy Learning Length Ligands Measurement Measures Mediating Memory Methods Microscopy Modification Morphology Mus Neck Neuraxis Neurobiology Neurons Pain Parents Peptides Photobleaching Photons Physiological Physiology Play Preparation Process Property Quantum Dots Reaction Time Research Research Personnel Research Training Role Shapes Signal Transduction Slice Sodium Specificity Spinal Structure Structure-Activity Relationship Surface Synapses Temperature Trauma Vertebral column chemical property design experience fascinate flexibility hippocampal pyramidal neuron insight nano nanoparticle nanosensors nervous system disorder neural circuit neuronal cell body novel painful neuropathy patch clamp research study response small molecule time use tool two-photon

项目摘要

DESCRIPTION (provided by applicant): This research plan proposes a major technical advancement in fluorescent imaging of ion dynamics by designing modular, tunable nanosensors with narrow emission spectra. Under two-photon microscopy, these nanosensors will quantitatively image the spatio-temporal dynamics of sodium fluxes in dendritic spines, which has never been done before. Dendritic spines are tiny, semi-autonomously neuronal compartments that exhibit a fascinating relationship between their structure and their function in processing synaptic signals. This dynamic structure-function relationship provides extraordinarily high input specificity while also allowing for rapid modifications that give rise t plasticity in neural circuits. Understanding spinal physiology may vastly enhance our causal knowledge for a broad range of diseases from Alzheimer's to neuropathic pain as well as basic processes in learning and memory. In order to gain be able to image sodium fluxes, we need to design fluorescent nanosensors that can enter into spines and rapidly measure local sodium concentrations. For this reason, we will use a novel design we call PUNQs for Photostable, Ultra-fast, Nano-optode, Quantum dots. These new PUNQs are modular, tunable, and have narrow emission spectra. Thus, with existing chemistry, they can be easily modifiable to study new ion and small-molecule targets, their dynamic ranges can be adjusted for the target analyte's physiologic concentration, and they can be multiplexed together. This research will produce new insight into the elusive dynamics of sodium in dendritic spines, and the PUNQ platform will be applicable to any research involving ion dynamics. The specific aims of this research are: 1) Designing PUNQs with optimal size and chemical properties to achieve physiologically-relevant analyte sensitivity and selectivity 2) Delivering PUNQs into small cellular subcompartments at effective concentrations. 3) Measuring dendritic and somatic Na+ fluxes in response to glutamatergic excitation at dendritic spines. This interdisciplinary research merges the Clark laboratory's experience with nanosensor development, the Bhatia laboratory's expertise in multifunctional nanoparticle development, and the Sabatini laboratory's expertise in neurobiology. The proposed research and training plan will elucidate the role of sodium in dendritic spines, and provide a high-value, flexible tool to study ion dynamics within individual cells. Finally, research will provide me with valuable experience that will prepare me for a future as an independent investigator in biomedical research.

描述（由申请人提供）：本研究计划提出了一个重大的技术进步，通过设计模块化的，可调的纳米传感器与窄发射光谱的离子动力学荧光成像。在双光子显微镜下，这些纳米传感器将定量成像树突棘中钠通量的时空动态，这是以前从未做过的。树突棘是微小的、半自主的神经元隔室，它们的结构和处理突触信号的功能之间存在着迷人的关系。这种动态的结构-功能关系提供了非常高的输入特异性，同时也允许快速修改，从而在神经回路中产生可塑性。了解脊柱生理学可能会极大地增强我们对从阿尔茨海默氏症到神经性疼痛以及学习和记忆基本过程的广泛疾病的因果知识。为了获得能够成像钠通量，我们需要设计荧光纳米传感器，可以进入脊椎并快速测量局部钠浓度。为此，我们将使用一种新颖的设计，我们称之为PUNQs，用于光稳定，超快，纳米光电二极管，量子点。这些新的PUNQ是模块化的、可调谐的，并且具有窄的发射光谱。因此，利用现有的化学方法，它们可以容易地被修改以研究新的离子和小分子目标，它们的动态范围可以针对目标分析物的生理浓度进行调整，并且它们可以被复用在一起。这项研究将对钠在树突棘中难以捉摸的动力学产生新的见解，PUNQ平台将适用于任何涉及离子动力学的研究。本研究的具体目标是：1）设计具有最佳尺寸和化学性质的PUNQ，以实现生理相关的分析物灵敏度和选择性2）以有效浓度将PUNQ递送到小细胞亚室中。 3)测量树突和体细胞Na+通量响应于树突棘的多巴胺能兴奋。这种跨学科的研究该公司将Clark实验室在纳米传感器开发方面的经验、Bhatia实验室在多功能纳米颗粒开发方面的专业知识以及Sabatini实验室在神经生物学方面的专业知识相结合。拟议的研究和培训计划将阐明钠在树突棘中的作用，并为研究单个细胞内的离子动力学提供高价值，灵活的工具。最后，研究将为我提供宝贵的经验，为我的未来做好准备。作为生物医学研究的独立调查员