Mathematical models of protein receptor trafficking in dendrites

树突中蛋白质受体运输的数学模型

• 批准号: 0813677
• 负责人: Paul Bressloff
• 金额: $ 27万
• 依托单位: University of Utah
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0813677&HistoricalAwards=false
• 关键词: Mathematical; models; protein; receptor; trafficking

Neurons are amongst the largest and most complex cells in biology. Their intricate geometry presents many challenges for cell function, in particular with regards to the efficient trafficking of newly synthesized proteins from the cell body or soma to distant locations on the axon or dendrites. In healthy cells, the regulation of protein trafficking within a neuron provides an important mechanism for modifying the strength of synaptic connections between neurons, and synaptic plasticity is generally believed to be the cellular substrate of learning and memory. On the other hand, various types of dysfunction in protein trafficking appear to be a major contributory factor to a number of neurodegenerative diseases associated with memory loss including Alzheimer?s. This project involves the mathematical modeling and analysis of one important aspect of protein trafficking, namely, the transportation of glutamate receptors in dendrites. These receptors mediate the majority of excitatory synaptic transmission in the central nervous system, and changes in the number of synaptic glutamate receptors contribute to the most studied forms of synaptic plasticity, namely, long term potentiation and depression (LTP and LTD). Building upon recent work of the PI, the research will consider a novel reaction-diffusion model of receptor trafficking that combines diffusion along the surface membrane of the cell membrane with biochemical processes within individual synapses. This mathematical model will be used to investigate the regulatory mechanisms that control the distribution of glutamate receptors along a dendrite under basal conditions, during synaptic plasticity and during neurodegeneration. A quantitative understanding of these regulatory mechanisms could help to identify important molecular and cellular processes underlying learning and memory in healthy brains, as well as memory-loss in diseased brains. The work will have a broader impact through its interdisciplinary training of graduate students and through the University of Utah?s Brain Institute, which plays a major educational role in promoting awareness and understanding within the local community.

神经元是生物学中最大、最复杂的细胞之一。它们错综复杂的几何形状给细胞功能带来了许多挑战，特别是在有效地将新合成的蛋白质从细胞体或胞体运输到轴突或树突上的远处位置方面。在健康细胞中，神经元内蛋白质运输的调节为改变神经元之间突触连接的强度提供了重要机制，突触可塑性通常被认为是学习和记忆的细胞底物。另一方面，各种类型的蛋白质转运障碍似乎是许多与记忆丧失相关的神经退行性疾病的主要因素，包括阿尔茨海默病？S。这个项目涉及蛋白质转运的一个重要方面的数学建模和分析，即树突中谷氨酸受体的运输。这些受体介导了中枢神经系统中大部分兴奋性突触传递，突触谷氨酸受体数量的变化有助于突触可塑性的研究最多的形式，即长时程增强和长时程增强和抑制(LTP和LTD)。在PI最近工作的基础上，这项研究将考虑一种新的受体运输的反应-扩散模型，该模型将沿细胞膜表面的扩散与单个突触内的生化过程相结合。这个数学模型将被用来研究在基础条件下、突触可塑性期间和神经变性期间控制谷氨酸受体沿树突分布的调节机制。对这些调控机制的定量了解可以帮助识别健康大脑学习和记忆的重要分子和细胞过程，以及疾病大脑的记忆丧失。这项工作将通过其对研究生的跨学科培训以及犹他大学S脑研究所产生更广泛的影响，该研究所在促进当地社区的意识和理解方面发挥着重要的教育作用。