Spatially realistic simulations of calcium dependent neurotransmitter release.

钙依赖性神经递质释放的空间真实模拟。

• 批准号: 7408354
• 负责人: Markus Dittrich
• 金额: $ 4.96万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-11 至 2010-01-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408354
• 关键词: Action Potentials; Algorithms; Binding; Buffers; Calcium; Calcium Channel; Calcium ion; Calcium-Sensing Receptors; Cells; Chromosome Pairing; Clinical Treatment; Complex; Computer Simulation; Development; Diffusion; Elements; Human; Human body; Investigation; Kinetics; Lead; Location; Mission; Modeling; Molecular; Nerve; Neurons; Neurophysiology - biologic function; Numbers; Pharmaceutical Preparations; Physiologic pulse; Physiological Processes; Pulse taking; Randomized; Research; Shapes; Signal Transduction; Simulate; Staging; Synapses; Synaptic Vesicles; Synaptic plasticity; Toxin; United States National Institutes of Health; Vesicle; insight; model development; nervous system disorder; neurotransmission; neurotransmitter release; programs; simulation; synaptic function

DESCRIPTION (provided by applicant): The proposed research aims to develop a comprehensive and spatially realistic computational model of action potential triggered, calcium dependent neurotransmitter release from synaptic vesicles. This model will provide unprecedented spatio-temporal insights into the physiological processes following the invasion of an action potential into a nerve terminal. Model development will proceed from an existing, spatially realistic baseline model of a single active zone, the specialized region within a nerve terminal that includes neurotransmitter release machinery. All simulations will be carried out with the program MCell which uses Monte Carlo algorithms to simulate molecular diffusion of calcium ions and buffer molecules, binding of calcium ions to receptors, and calcium channel gating inside arbitrary complex cellular spaces. Guided by experimental input, we will investigate the effect of perturbations and combinations thereof to the existing baseline model such as changes in the location, arrangement (homogeneous, randomized, clustered), and number of calcium channels; drug treatments (3,4-diaminopyridine, roscovitin) influencing the calcium channel kinetics and action potential shape; toxin treatments blocking fractions of calcium channels; and the effect of mobile buffer and/or mixtures of static and mobile buffer on vesicle release. These studies will lead to significant improvements of the baseline model and, thereby, set the stage for an investigation of short term synaptic plasticity via paired pulse action potentials. We will first identify mechanisms that give rise to the experimentally observed values for paired pulse facilitation and then investigate the effect of changes in the interstimulus interval and drug treatments on paired pulse facilitation. Clearly, the importance of elucidating the key elements of paired pulse facilitation and thereby synaptic plasticity for a more comprehensive understanding of human neural function can not be underestimated. The proper and faithful transmission of nerve signals along neurons in the human body is crucial for survival. Synapses constitute the connecting elements between neurons and cells they innervate and many debilitating neurological disorders are caused by synaptic dys-function. Hence, a proper understanding of synaptic function is crucial for the development of clinical treatments for neurological diseases. The proposed research will directly contribute to our understanding of synaptic function and is therefore directly relevant to the mission of the NIH.

描述（由申请人提供）：拟议的研究旨在开发一个全面的和空间现实的计算模型的动作电位触发，钙依赖性神经递质从突触囊泡释放。该模型将提供前所未有的时空洞察力的生理过程后，入侵的动作电位到神经末梢。模型开发将从一个现有的，空间上现实的基线模型的一个单一的活动区，专门的区域内的神经末梢，包括神经递质释放机制。所有模拟将使用程序MCell进行，该程序使用蒙特卡罗算法模拟钙离子和缓冲液分子的分子扩散、钙离子与受体的结合以及任意复杂细胞空间内的钙通道门控。在实验输入的指导下，我们将研究扰动及其组合对现有基线模型的影响，例如位置、布置（均质、随机、聚类）和钙通道数量;药物治疗（3，4-二氨基吡啶，roscovitin）影响钙通道动力学和动作电位形状;以及移动的缓冲液和/或静态和移动的缓冲液的混合物对囊泡释放的影响。这些研究将导致基线模型的显著改进，从而为通过成对脉冲动作电位研究短期突触可塑性奠定基础。我们将首先确定产生配对脉冲易化的实验观察值的机制，然后研究刺激间隔和药物治疗对配对脉冲易化的影响。显然，阐明成对脉冲易化的关键要素，从而突触可塑性的人类神经功能的更全面的理解的重要性不能低估。神经信号在人体内沿着沿着神经元的正确和忠实的传输对生存至关重要。突触构成神经元和它们所支配的细胞之间的连接元件，并且许多使人衰弱的神经系统疾病是由突触功能障碍引起的。因此，正确理解突触功能对于神经系统疾病临床治疗的发展至关重要。这项拟议中的研究将直接有助于我们对突触功能的理解，因此与NIH的使命直接相关。