National Biomedical Computation Resource - Competitive Revision Supplement

国家生物医学计算资源 - 竞争性修订补充材料

基本信息

批准号：
8416525
负责人：
PETER William ARZBERGER
金额：
$ 36.76万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-05-06 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8416525
关键词：
3-Dimensional Actins Action Potentials Address Affect Allosteric Regulation Architecture Automobile Driving Binding Biological Biological Models Biomechanics Biomedical Computing Biomedical Research Biophysics Cardiac Cardiomyopathies Cell model Cells Code Complex Computer Simulation Computer software Coupling Cyclic AMP-Dependent Protein Kinases Defect Development Disease Electrons Electrophysiology (science)Equation Feedback Functional disorder Generations Goals Head Heart Heart Diseases Heart failure Hypertrophic Cardiomyopathy Image Individual Information Technology Kinetics Lead Libraries Measurement Mechanics Mediating Methods Microfilaments Mission Modeling Molecular Molecular Conformation Molecular Models Mus Muscle Muscle Cells Mutation Myocardial Myopathy Myosin ATPase Organ Pathology Performance Phenotype Physics Physiology Process Progress Reports Property Protein Dephosphorylation Proteins Publishing Pythons Regulation Research Research Infrastructure Research Personnel Resources Role Sarcomeres Scientist Signal Transduction Simulate Site-Directed Mutagenesis Striated Muscles Structure System Tail Technology Thermodynamics Thin Filament Tissue Model Tissues Transport Process Tropomyosin Troponin Troponin C Ventricular Work body system computerized data processing effective therapy genetic regulatory protein innovation markov model molecular dynamics molecular modeling multi-scale modeling protein complex public health relevance research and development simulation tool

项目摘要

DESCRIPTION (provided by applicant): The mission of the National Biomedical Computation Resource (NBCR) is to conduct, catalyze, and enable biomedical research by harnessing forefront information technologies to advance mechanistic understanding in multi-scale biomedical problems that integrate diverse structural and functional measurements and span scales of biological organization from molecule to organ system. A central theme of NBCR has been the development and deployment of tools and infrastructure that enable biomedical problems to be addressed using mechanistic, structure- and physics-driven computational models that span scales of biological organization from atomistic simulations of molecular dynamics to continuum simulations of organ physiology and pathophysiology. We have been developing new modeling methods and tools that fill gaps in our ability to bridge critical mesoscales such as the macromolecular (nm) to subcellular (pm) levels. Excellent progress has been made building structurally detailed 3-D models of subcellular architecture from electron tomographic image volumes and using these to simulate transport and signaling processes. But to span from molecular to whole cell, tissue and organ scales other approaches will also be needed. The present supplementary revision application proposes to develop new multi-scale modeling tools and methods that: (1) Allow Markov models (MM) of molecular states to be defined using molecular simulations including molecular dynamics (MD), and Brownian dynamics (BD) models; (2) Facilitate the inclusion of Markov models into systems models of cell signaling, electrophysiology and mechanics suitable for use in multiscale models of cell, tissue and organ biomechanics and biophysics. The goal of this competitive revision application is to develop new multiscale modeling tools and methods that will help bridge the gap between molecular models of individual sarcomeric protein components including actin, myosin and components of the troponin-tropomyosin regulatory complex and cellular models of whole sarcomere activation and mechanics in striated muscle. We also identify other applications ofthe proposed new tools including studies on the role of sarcomeric mutations in muscle diseases and on the function of protein kinase A.

描述（由申请人提供）：国家生物医学计算资源（NBCR）的使命是通过利用前沿信息技术来促进、促进和实现生物医学研究，以促进对多尺度生物医学问题的机械理解，这些问题整合了不同的结构和功能测量并跨越从分子到器官系统的生物组织规模。 NBCR 的中心主题是开发和部署工具和基础设施，使生物医学问题能够使用机械、结构和物理驱动的计算模型来解决，这些模型跨越生物组织的尺度，从分子动力学的原子模拟到器官的连续模拟生理学和病理生理学。我们一直在开发新的建模方法和工具，以填补我们在关键介尺度（例如大分子（nm）到亚细胞（pm）水平）之间架起桥梁的能力空白。利用电子断层扫描图像体积构建结构详细的亚细胞结构 3D 模型，并使用这些模型来模拟传输和信号传导过程，已经取得了巨大进展。但要从分子扩展到整个细胞、组织和器官尺度，还需要其他方法。目前的补充修订申请建议开发新的多尺度建模工具和方法，这些工具和方法：（1）允许使用包括分子动力学（MD）和布朗动力学（BD）模型在内的分子模拟来定义分子状态的马尔可夫模型（MM） ; (2) 促进将马尔可夫模型纳入细胞信号传导、电生理学和力学的系统模型中，适用于细胞、组织和器官生物力学和生物物理学的多尺度模型。这项竞争性修订申请的目标是开发新的多尺度建模工具和方法，以帮助弥合单个肌节蛋白成分（包括肌动蛋白、肌球蛋白和肌钙蛋白-原肌球蛋白调节复合物成分）的分子模型与整个肌节激活的细胞模型之间的差距。和横纹肌力学。我们还确定了所提出的新工具的其他应用，包括肌节突变在肌肉疾病中的作用和蛋白激酶 A 功能的研究。