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 信号传导 Kekenes-Huskey，肯塔基大学PM。通过探测细胞内钙信号传导和传感计算钙信号传导调节多种组织类型和物种的生物功能， 2+ 但已知控制 Ca 依赖性信号传导效率的几个因素对计算机和计算机都提出了挑战我们对其中细微差别的理解存在重大差距。蛋白质结构和动力学以及它们的细胞内分布从根本上影响重要 2+ 过程包括 1) Ca 在局部细胞内区域积聚 2) 蛋白质如何结合 2+ 2+ Ca 具有高亲和力 3) Ca“传感器”蛋白调节信号级联的详细知识。这些主题及其相互依赖性将产生我们如何看待生物学、生理学、计算机模拟在这方面很有吸引力，两者都可以描述现象。难以通过实验直接解决，也难以形成跨领域的完整概念模型然而，这些基本主题存在一些突出的障碍，使得这种变革性的模拟成为可能。其中，减少模型涉及的棘手计算费用。精细的细节过程，例如由亚纳米到微米尺度、原子尺度控制的传输形成离子/蛋白质结合的热力学因素，以及促进蛋白质/蛋白质结合的长程力信号通路可能是当今生物物理学中最重要的挑战，在这项提案中，我们概述了七项。多尺度算法的进步将缓解这一挑战，同时提供对重要问题的洞察 2+ Ca 驱动的协调生命的过程：主题 1 在分子水平上调整 Ca2+ 传感和响应在这个主题中，我们将。开发新的范式来理解自然控制特异性和动力学的技巧 2+ Ca 传感功能。主题 2 自动检测心脏疾病相关形态变化 2+ 细胞及其对钙稳态的影响在这个主题中，我们的实验室将利用大量的研究成果。未充分利用显微镜数据来回答有关细胞内组织作用的问题 2+ 塑造 Ca 信号传导。主题 3 通过 P2X4 受体进行细胞尺度控制的分子机制。主题，我们将在分子尺度蛋白质结构/功能及其它们之间建立牢固的联系细胞尺度信号转导结果的控制。 1