Mathematical models of protein receptor trafficking in dendrites

神经元是生物学中最大、最复杂的细胞之一。它们复杂的几何形状对细胞功能提出了许多挑战，特别是关于从新合成的蛋白质从细胞体或体细胞到轴突或树突上的遥远位置的有效运输。在健康细胞中，神经元内蛋白质运输的调节为神经元之间突触连接的强度提供了重要的机制，突触可塑性通常被认为是学习和记忆的细胞基质。另一方面，各种类型的蛋白质运输功能障碍似乎是许多与记忆丧失相关的神经退行性疾病（包括阿尔茨海默氏症）的主要促成因素。该项目涉及蛋白质运输的一个重要方面的数学建模和分析，即谷氨酸受体在树突中的运输。这些受体介导中枢神经系统中大多数兴奋性突触传递，突触谷氨酸受体数量的变化有助于突触可塑性的研究形式，即长期增强和抑制（LTP和LTD）。在PI最近工作的基础上，该研究将考虑一种新的受体运输的反应扩散模型，该模型将细胞膜表面膜的扩散与单个突触内的生化过程结合起来。该数学模型将用于研究在基础条件下、突触可塑性和神经退行性过程中谷氨酸受体沿树突分布的调控机制。对这些调节机制的定量理解可以帮助确定健康大脑中学习和记忆的重要分子和细胞过程，以及患病大脑中的记忆丧失。这项工作将通过对研究生的跨学科培训以及犹他大学（University of Utah）产生更广泛的影响。该研究所在促进当地社区的认识和理解方面发挥着重要的教育作用。

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.