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

• 批准号: 9982032
• 负责人: Peter Michael Kekenes-Huskey
• 金额: $ 32.29万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982032
• 关键词: Affect; Affinity; Algorithms; Binding Proteins; Biological Process; Biology; Biophysics; Calcium Signaling; Cardiac; Cell physiology; Cells; Computer Simulation; Data; Dependence; Detection; Disease; Functional disorder; Health; Homeostasis; Immune response; Ions; Kentucky; Kinetics; Knowledge; Lead; Life; Link; Malignant Neoplasms; Microscopy; Modeling; Molecular; Morphology; Motivation; Muscle Contraction; Nature; Nervous System Physiology; Outcome; Physiology; Process; Protein Dynamics; Proteins; Role; Shapes; Signal Pathway; Signal Transduction; Signaling Protein; Specificity; Structural Protein; Thermodynamics; Tissues; Universities; combat; computerized tools; cost; hormone regulation; human disease; innovation; insight; molecular scale; nanometer; novel; novel strategies; protein structure; protein structure function; receptor; response; sensor; simulation

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

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