权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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个以上细胞内Ca信号传导Kekenes-Huskey，PM。肯塔基州大学探测细胞内钙信号和传感通过计算钙信号传导调节广泛的组织类型和物种的生物功能， 2个以上但已知的几个控制钙依赖性信号传导效率的因素挑战了这两种复合物，实验和实验研究。在我们理解的细微差别，蛋白质的结构和动力学以及它们的细胞内分布影响着根本重要的 2个以上过程包括1）Ca如何在局部细胞内区域累积2）蛋白质结合 2+ 2+ 3）Ca“传感器”蛋白调节信号级联。详细了解这些主题及其相互依赖性将产生新的范式，我们如何看待生物学，生理学，与健康计算机模拟在这方面是有吸引力的，无论是描述现象，很难直接通过实验解决，也很难形成综合概念模型，这些潜在的主题。然而，几个突出的障碍使这种变革性的模拟成本过高。其中，减少涉及模型的棘手的计算费用，精细的细节过程，如由亚纳米到微米尺度、原子尺度形成离子/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面临的最大挑战。在这篇文章中，我们提出了七个问题-- 所有多尺度算法的进步，将缓解这一挑战，同时提供重要的洞察力 2个以上钙驱动的过程，编排生活：主题1在分子水平上调节Ca 2+感受和反应。在这个主题中，我们将开发新的范例，以了解自然界控制特异性和动力学的技巧， 2个以上 Ca传感功能。主题2心脏疾病相关形态学变化的自动检测 2个以上细胞及其对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显微镜数据来回答有关细胞内组织作用的问题 2个以上在塑造Ca信号方面。主题3通过P2 X4受体控制细胞规模的分子机制。在这主题，我们将建立分子尺度蛋白质结构/功能与其控制细胞规模的信号结果。 1