CAREER: The Dynamics of IP3-Sensitive Calcium Release Sites

职业：IP3 敏感钙释放位点的动态

• 批准号: 0133132
• 负责人: Gregory Conradi Smith
• 金额: $ 50万
• 依托单位: College of William and Mary
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-15 至 2008-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0133132&HistoricalAwards=false
• 关键词: CAREER; Dynamics; IP3; Sensitive; Calcium

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.

该教师早期职业发展奖支持威廉和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计算模型的动态Ca 2+调节在IP 3敏感的Ca 2+释放网站，其中包括1）随机激活和IP 3R与IP 3多样性的当前知识一致的失活和2）一个现实的帐户细胞内Ca 2+的缓冲扩散导致合作IP 3R活动。 该模型将用于测试四个具体假设。 首先，1型IP 3R的最佳密度导致最大释放位点活化（但对于2型IP 3R并非如此）。 第二，Ca 2+缓冲液影响释放位点激活的方式依赖于密度和亚型的IP 3Rs。 第三，释放位点表现出不同的动力学激活和失活取决于IP 3R亚型。 第四，Ca 2+调节的动态在释放网站与紧密聚集的IP 3Rs是很好的近似简化模型，利用稳态Ca 2+微域理论。 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IP 3敏感的Ca 2+释放位点的统计特性以及IP 3R聚类对全球Ca 2+响应的影响有关。 教育活动包括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定量方法的课程开发。 一个新的课程，题为“细胞生物物理学和建模”强调扩散，膜运输，质量作用动力学，电压和配体门控离子通道，全细胞电流，房室建模，质膜电兴奋性和细胞信号转导动力学的单通道记录。 第二个新的课程，“生物信息学导论”，暴露生物学专业（在计算机编程的最低背景）的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。 这两个课程包括一个综合计算机实验室。这个教师早期职业发展奖支持在威廉和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，称为内质网（ER）的细胞器具有类似于神经元的可兴奋膜的整合和再生特性。 虽然已经通过开发基于分子机制的Ca 2+处理的全细胞模型获得了对ER“Ca 2+兴奋性”的洞察，但是迄今为止全细胞模型的局限性是假设IP 3受体（IP 3R）通过大量（或平均）胞质Ca 2+浓度全局偶联。 为了克服这些限制，Smith教授正在开发IP 3敏感的Ca 2+释放位点的Ca 2+调节动力学的计算模型，该模型专注于由细胞内Ca 2+扩散介导的IP 3R的局部偶联，这是细胞信号传导的一个基本和重要方面。 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IP 3敏感的Ca 2+释放位点的统计特性以及IP 3R聚类对全球Ca 2+响应的影响有关。 教育活动包括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定量方法的课程开发。 目前正在开发两门新课程：“细胞生物物理学和建模”和“生物信息学入门”，这两门课程都有一个综合计算机实验室。