Explore fundamental aspects of neurotransmission with multifunctional nanosensor

使用多功能纳米传感器探索神经传递的基本方面

• 批准号: 8146810
• 负责人: Qi Zhang
• 金额: $ 234万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146810
• 关键词: Acculturation; Acids; Address; Behavior; Biological Process; Brain; Clinic; Cognition; Complex; Comprehension; Coupling; Detection; Diagnostic; Discipline; Electrophysiology (science); Elements; Image; In Situ; Investigation; Kinetics; Link; Measurement; Modification; Nanotechnology; Neuraxis; Neurons; Neurosciences; Neurotransmitter Receptor; Neurotransmitters; Noise; Physiology; Proteins; Quantum Dots; Reporting; Research; Resolution; Retrieval; Scientific Advances and Accomplishments; Scientist; Signal Transduction; Structure; Surface; Synapses; Synaptic Cleft; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Testing; Therapeutic; Time; Transplantation; Vesicle; Work; abstracting; aptamer; in vivo; interest; nanosensors; nervous system disorder; neurotransmission; neurotransmitter release; patch clamp; postsynaptic; presynaptic; public health relevance; quantum; receptor; spatiotemporal; success; tool; trafficking

DESCRIPTION (Provided by the applicant) Abstract: The brain is an extraordinarily complex network made of billions of neurons. The synapse, the contact point between neurons, has been the centre of interest for decades. Starting with Ram¿n Cajal, scientists have been borrowing tools from other disciplines to study this tiny, but crucial structure. The breakthrough truly came after the introduction of electrophysiology, which allows the measurement of neuronal activity at an extremely high signal-to-noise ratio. It became clear that synaptic transmission is conducted via the presynaptic release of neurotransmitters from synaptic vesicles and the subsequent activation of postsynaptic receptors. So far, changes in synaptic transmission have generally been attributed to the modification of postsynaptic receptors. Nevertheless, newly emerged evidence has demonstrated that the receptors do not act autonomously and synaptic vesicles indeed make significant contribution to synaptic plasticity. Despite great interest and effort, the lack of a direct and precise measurement obstructs further investigation of synaptic vesicles and thus impedes a complete comprehension of such mutual modulation. Borrowing from nanotechnology, I devised a single-vesicle imaging approach using quantum dot (Qdot), which for the first time provides superior spatiotemporal resolution matching or even exceeding that of patch-clamp recording. With this original tool, I unveiled the existence, kinetics and regulatory mechanisms of an unconventional mode of vesicle reuse in mammalian central synapses. Here, I propose that synaptic modulation is composed of a sequence of coordinated and equally profound changes at both pre- and postsynaptic terminals. To test it, I will develop ""smart"" nanosensors made of Qdots and aptamers, a new class of synthetic oligonucleic acids. These nanosensors can precisely target designated synaptic structures or proteins and simultaneously report orchestrated pre- and postsynaptic changes in situ. To demonstrate the power of this revolutionary tool, I will deploy it to address some fundamental and long-standing questions in synaptic physiology, such as the coupling of vesicle reacidification and refilling after retrieval, the fluctuation of neurotransmitter concentration around the synaptic cleft, and the acculturation of presynaptic vesicles and postsynaptic receptors. Because Qdots are ideal for in vivo imaging, I will screen for aptamers that can deliver these nanosensors to designated synapses in the intact brain such that synaptic transmission can be studied in defined neuronal circuits. The success of this project promises a quantum leap in our understanding of neurotransmission. The technical and scientific advances made from this work can be readily transplanted to other biomedical fields because vesicles turnover and surface receptor trafficking are widely involved in almost all biological processes. Moreover, both Qdots and aptamers are modular units that can be linked with all kinds of diagnostic or therapeutic molecules. Therefore, this project has a broad impact beyond neuroscience. . Public Health Relevance: Synapse is the most essential element for transmitting information in brain neuronal network which is responsible for our cognition and daily behavior. By inventing and deploying multifunctional nanoporbes, we will investigate the most fundamental aspects of synaptic transmission including synaptic vesicles, neurotransmitters and receptors in mammalian central nervous system. As these components of synapses evidently became abnormal in most neurological disorders, our finding will bridge the gap between basic and clinic research for better understanding, detection, characterization, and treatment of neurological disorders.

描述（申请人提供） 摘要：大脑是一个由数十亿个神经元组成的非常复杂的网络。几十年来，突触是神经元之间的接触点。从公羊n Cajal开始，科学家一直从其他学科借用工具来研究这种微小但至关重要的结构。突破确实是在引入电生理学之后的，这允许以极高的信噪比测量神经元活性。很明显，合成传播是通过突触前释放神经递质从合成蔬菜中释放出来的，并随后激活突触后受体。到目前为止，突触传播的变化通常归因于突触后受体的修饰。然而，新出现的证据表明，受体并非自主作用，合成蔬菜确实对合成可塑性做出了重大贡献。尽管非常兴趣和精力，但缺乏直接和精确的测量仍阻碍了对合成蔬菜的进一步研究，因此阻碍了对这种相互调制的完全理解。从纳米技术借用，我使用Quantum Dot（QDOT）设计了一种单维成像方法，该方法首次提供了较高的空间时间分辨率匹配，甚至超过了贴片钳记录。有了这个原始工具，我揭示了哺乳动物中央突触中囊泡重复使用的非常规模式的存在，动力学和调节机制。在这里，我提出合成调制是由前后突触后末端的一系列协调和同样深刻的变化组成的。为了进行测试，我将开发由QDOTS和APTAMER制成的纳米传感器，这是一种新的合成寡核酸。这些纳米传感器可以精确靶向指定的合成结构或蛋白质，并简单地报告原位策划的前和突触后变化。为了展示这种革命性工具的力量，我将其部署以解决一些突触生理学中的一些基本和长期存在的问题，例如蔬菜反应的偶联和检索后的补充，在合成裂解周围的神经递质浓度的波动以及征服者的征收蔬菜和后蔬菜受体受体。由于QDOTS是体内成像的理想选择，因此我将筛选可以将这些纳米传感器传递到完整大脑中指定的突触的适体，以便可以在定义的神经元圆圈中研究合成传递。该项目的成功有望在我们对神经传递的理解中取得巨大的飞跃。这项工作的技术和科学进步很容易被移植到其他生物医学领域，因为蔬菜的离职和表面受体运输几乎与所有生物学过程都广泛涉及。此外，QDOTS和APTAMER都是模块化单元，可以与各种诊断或治疗性分子联系起来。因此，该项目超出了神经科学。 。 公共卫生相关性：突触是脑神经元网络中传输信息的最重要元素，该信息负责我们的认知和日常行为。通过发明和部署多功能纳米孔，我们将研究突触传播的最根本方面，包括哺乳动物中枢神经系统中的突触蔬菜，神经递质和受体。随着这些突触的这些成分在大多数神经系统疾病中显然变得异常，我们的发现将弥合基础研究和临床研究之间的差距，以更好地理解，检测，表征和治疗神经系统疾病。