CAREER: The Dynamics of IP3-Sensitive Calcium Release Sites

这一教师早期职业发展奖支持威廉与玛丽学院计算细胞生物学跨学科领域的综合研究和教育活动。史密斯教授正在开发一个关于IP3敏感的钙释放部位的钙调节动力学的计算模型，该模型包括：1)IP3R的随机激活和失活，与目前对IP3多样性的认识一致；2)对导致IP3R协同活性的细胞内钙的缓冲扩散进行现实的解释。这个模型将被用来检验四个具体的假设。首先，1型IP3R的最佳密度导致最大的释放位点激活(但对于2型IP3R则不是这样)。第二，钙离子缓冲液以依赖于IP3R密度和亚型的方式影响释放位激活。第三，释放部位根据IP3R亚型的不同表现出不同的激活和失活动力学。第四，利用稳态钙微域理论的简化模型很好地模拟了IP3R紧密聚集的释放部位的钙调节动力学。此外，史密斯教授正在指导几个跨学科的研究生/本科生研究项目，这些项目与IP3敏感的钙释放位点的统计特性以及IP3R聚集对全球钙反应的影响有关。教育活动包括课程开发，旨在增加威廉和玛丽的研究生和本科生接触细胞和分子生物学的定量方法。一门名为“细胞生物物理与建模”的新课程强调扩散、膜传输、质量作用动力学、电压门控和配体门控离子通道的单通道记录、全细胞电流、隔室模型、质膜电兴奋性以及细胞信号转导的动力学。第二门新课程“生物信息学入门”让生物学专业的学生(计算机编程背景最低)学习计算分子生物学的基本算法，包括序列比较、片段组装、系统发育树构建和二级结构预测。这两个课程都包括一个综合计算机实验室。这一教师早期职业发展奖支持威廉与玛丽学院的计算细胞生物学研究和教育。在大多数细胞类型中，一个称为内质网(ER)的细胞器具有整合和再生特性，类似于神经元的可兴奋膜。虽然对内质网“钙离子兴奋性”的洞察是通过发展基于分子机制的钙离子处理的全细胞模型来获得的，但迄今为止全细胞模型的局限性是假设IP3受体(IP3R)是通过胞内整体(或平均)钙离子浓度而全局偶联的。为了克服这些局限性，Smith教授正在开发对IP3敏感的钙释放部位的钙调节动力学的计算模型，这些模型侧重于细胞内钙的扩散介导的IP3R的局部耦合，这是细胞信号的一个基本和重要的方面。史密斯教授还指导了几个跨学科的研究生/本科生研究项目，这些项目与IP3敏感的钙释放位点的统计特性以及IP3R聚集对全球钙反应的影响有关。教育活动包括课程开发，旨在增加威廉和玛丽的研究生和本科生接触细胞和分子生物学的定量方法。两门新课程正在开发中：“细胞生物物理学和建模”和“生物信息学入门”，这两门课程都涉及一个综合计算机实验室。

This faculty early career development award supports integrated research and educational activities in the interdisciplinary area of computational cell biology at the College of William and Mary. Professor Smith is developing a computational model of the dynamics of Ca2+ regulation at IP3-sensitive Ca2+ release sites that includes both 1) stochastic activation and inactivation of IP3Rs consistent with current knowledge of IP3 diversity and 2) a realistic account of the buffered diffusion of intracellular Ca2+ leading to cooperative IP3R activity. This model will be used to test four specific hypotheses. First, an optimal density of type 1 IP3Rs leads to maximum release site activation (but not so for type 2 IP3Rs). Second, Ca2+ buffers influence release site activation in a manner dependent on density and subtype of IP3Rs. Third, release sites exhibit distinct kinetics of activation and inactivation depending on IP3R subtype. Fourth, the dynamics of Ca2+ regulation at release sites with tightly clustered IP3Rs are well-approximated by reduced models utilizing steady-state Ca2+ microdomain theory. In addition, Prof. Smith is directing several interdisciplinary graduate/undergraduate research projects related to the statistical properties of IP3-sensitive Ca2+ release sites and the effect of IP3R clustering on global Ca2+ responses. Educational activities include curriculum development intended to increase the exposure of graduate and undergraduate students at William and Mary to quantitative approaches in cell and molecular biology. A new course entitled "Cellular Biophysics and Modeling" emphasizes diffusion, membrane transport, mass action kinetics, single channel recording of voltage- and ligand-gated ion channels, whole cell currents, compartmental modeling, plasma membrane electrical excitability, and dynamics in cell signal transduction. A second new course, "Introductory Bioinformatics," exposes biology majors (with minimal background in computer programming) to the basic algorithms of computational molecular biology including sequence comparison, fragment assembly, phylogenetic tree construction, and secondary structure prediction. Both courses include an integrated computer laboratory. This faculty early career development award supports computational cell biology research and education at the College of William and Mary. In most cell types an organelle called the endoplasmic reticulum (ER) has integrative and regenerative properties analogous to the excitable membranes of neurons. While insight into ER "Ca2+ excitability" has been obtained through the development of whole cell models of Ca2+ handling that are based on molecular mechanisms, a limitation of whole cell models to date is the assumption that IP3 receptors (IP3Rs) are globally coupled by the bulk (or average) cytosolic Ca2+ concentration. In order to overcome these limitations, Prof. Smith is developing computational models of the dynamics of Ca2+ regulation at IP3-sensitive Ca2+ release sites that focus on local coupling of IP3Rs mediated by the diffusion of intracellular Ca2+, a fundamental and significant aspect of cell signaling. Prof. Smith is also directing several interdisciplinary graduate/undergraduate research projects related to the statistical properties of IP3-sensitive Ca2+ release sites and the effect of IP3R clustering on global Ca2+ responses. Educational activities include curriculum development intended to increase the exposure of graduate and undergraduate students at William and Mary to quantitative approaches in cell and molecular biology. Two new courses are being developed: "Cellular Biophysics and Modeling" and "Introductory Bioinformatics," both of which involve an integrated computer laboratory.