PROBING CELLULAR INTRACELLULAR CALCIUM SIGNALING AND SENSING THROUGH COMPUTATION

通过计算探测细胞内钙信号传导和传感

基本信息

批准号：
10222716
负责人：
Peter Michael Kekenes-Huskey
金额：
$ 32.59万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-04-30
项目状态：
已结题

项目摘要

2+ Intracellular Ca signaling Kekenes-Huskey, PM. University of Kentucky Probing cellular intracellular calcium signaling and sensing through computation Calcium signaling regulates biological function across a broad range of tissue types and species, 2+ but several factors known to control Ca -dependent signaling efﬁciency have challenged both compu- tational and experimental inquiry. There are signiﬁcant gaps in our understanding of how nuances in protein structure and dynamics as well as their intracellular distribution affect fundamentally important 2+ processes including how 1) Ca accumulates within localized intracellular regions 2) proteins bind 2+ 2+ Ca with high afﬁnity 3) Ca 'sensor' proteins regulate signaling cascades. Detailed knowledge about these topics and their inter-dependencies would yield new paradigms in how we view biology, physiology, and health. Computer simulations are attractive in this regard, both for describing phenomena that are difﬁcult to directly resolve experimentally, as well as forming integrative conceptual models spanning these underlying topics. However, several prominent hurdles render such transformative simulations cost-prohibitive. Among these, reducing the intractable computational expense involved with model- ing ﬁne detail processes like transport governed by sub-nanometer to micron scales, atomistic-scale thermodynamic factors shaping ion/protein binding, and long-range forces that promote protein/protein signaling pathways, is likely the foremost challenge in biophysics today. In this proposal, we outline sev- eral multi-scale algorithmic advances that will ease this challenge, while providing insight into important 2+ Ca -driven processes that orchestrate life: Theme 1 Tuning Ca2+ sensing and response at the molecular level. In this theme, we will develop new paradigms for understanding nature's tricks for controlling speciﬁcity and kinetics in 2+ Ca sensing functions. Theme 2 Automated detection of disease-associated morphological changes in cardiac 2+ cells and their inﬂuence on Ca homeostasis. In this theme, our lab will leverage troves of underutilized microscopy data to answer questions regarding the role of intracellular organization 2+ in shaping Ca signaling. Theme 3 Molecular mechanisms of cellular-scale control via the P2X4 receptor. In this theme, we will establish strong links between molecular scale protein structure/function and their control of cellular-scale signaling outcomes. 1

2+ 细胞内Ca信号Kekenes-Huskey，PM。肯塔基大学探测细胞内钙信号传导和通过计算钙信号传导调节各种组织类型和物种的生物学功能， 2+ 但是，已知控制CA依赖性信号效率的几个因素对两者都有质疑态度和实验性查询。我们对中细微差别的理解有显着的差距蛋白质结构和动力学以及它们的细胞内分布对根本上重要 2+ 包括1）CA在局部细胞内区域中积累的过程2）蛋白质结合 2+ 2+ Ca具有较高的aftimity 3）Ca“传感器”蛋白调节信号级联。详细的知识这些主题及其相互依存关系将产生我们如何看待生物学，生理学，和健康。在这方面，计算机模拟都很有吸引力，既是描述现象很难直接通过实验解决，并形成跨越的综合概念模型这些基本主题。但是，几个突出的障碍进行了这种变革性模拟成本良好。其中，减少了与模型有关的棘手的计算费用详细的流程，例如由子纳米计到微米尺度的运输，原子尺度塑造离子/蛋白质结合的热力学因子以及促进蛋白质/蛋白质的远程力信号通路，可能是当今生物物理学中最重要的挑战。在此提案中，我们概述了错误的多尺度算法进步，可以缓解这一挑战，同时提供对重要的洞察力 2+ CA驱动的过程，这些过程策划了生活：主题1调整Ca2+敏感性和分子水平的响应。在这个主题中，我们将开发新的范式来理解自然的技巧，以控制特定的城市和动力学 2+ CA感应功能。主题2心脏疾病相关形态变化的自动检测 2+ 细胞及其对CA稳态的影响。在这个主题中，我们的实验室将利用未充分利用的显微镜数据回答有关细胞内组织作用的问题 2+ 在塑造CA信号传导中。主题3通过P2X4受体控制细胞尺度控制的分子机制。在这个主题，我们将在分子尺度蛋白结构/功能及其功能之间建立牢固的联系控制细胞尺度信号传导结果。 1