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Multiscale Modeling of Sickle Cell Anemia: Methods and Validation

镰状细胞性贫血的多尺度建模：方法和验证

基本信息

批准号：
9315872
负责人：
Ming Dao
金额：
$ 77.81万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9315872
关键词：
Adhesions Adhesives Adopted Affect African American Algorithms Animal Model Arteries Biochemical Birth Blood Blood Cells Blood flow Cell Shape Cell Wall Cell membrane Cell model Cells Cellular Morphology Cerebral Malaria Child Companions Coupled Coupling Cytoskeleton Cytosol Data Development Endothelium Erythrocytes Event Fetal Hemoglobin Generations Growth Hematological Disease Hemoglobin Hydration status Hypoxia Individual Investigation Investigational Therapies Lasers Ligands Link Lipid Bilayers Literature Malaria Measurement Measures Mechanics Membrane Methodology Methods Microcirculation Microfluidics Microscopy Modality Modeling Modification Modulus Molecular Molecular Conformation Morbidity - disease rate Morphology Motion Optics Pathogenesis Patients Pharmaceutical Preparations Phase Plasma Polymers Polynomial Models Process Reporting Resistance Rheology Shapes Sickle Cell Sickle Cell Anemia Signal Pathway Site Software Tools Structure System Techniques Therapeutic Intervention Time Transfusion Uncertainty Validation Vascular Cell Adhesion Molecule-1 Work base biophysical properties drug abuse prevention experimental study hydroxyurea innovation laser tweezer men who have sex with men molecular dynamics mortality multi-scale modeling nanomechanics online repository particle polymerization public health relevance response sickling simulation spatiotemporal

项目摘要

DESCRIPTION (provided by applicant): The objective of this project is to develop a validated multiscale modeling methodology for quantifying the biophysical characteristics of sickle cell disease (SCD) -- a hematological disorder that affects tens of thousands of people in US with one in every 500 African-American births resulting in a child with SCD. The pathogenesis of SCD results from (1) irregular red blood cell (RBC) shapes due to hemoglobin polymerization inside the RBCs; (2) stiffening of the RBC membrane; and (3) adhesion of sickle RBCs to the endothelium and the other blood cells. The combination of these phenomena results in vaso-occlusive events or "crises" responsible for the majority of morbidity and mortality associated with SCD but little is certain about the proximal causes or the circumstances in which they occur. The spatio-temporal scales involved in accurately modeling SCD blood flow and vaso-occlusion span at least four orders of magnitude, hence new numerical methods are needed to simulate such multiscale phenomena. We present a general methodology based on 3D dissipative particle dynamics (DPD) to model flow and soft matter seamlessly, i.e., RBCs and other blood cells, blood plasma, cytosol, hemoglobin polymerization, and adhesive dynamics. DPD can be interfaced with molecular dynamics (MD) and with continuum-based description (e.g. Navier-Stokes) based on the triple-decker algorithm we have developed in order to capture molecular details or for computational efficiency in simulating large arteries or networks, respectively. We adopt the same approach here that has proven very effective in our previous work on malaria, namely that models for single RBCs (healthy or sickled), informed and validated from comprehensive single-cell measurements, will be used to predict the collective dynamics and rheology of SCD blood flow. We also present a systematic experimental plan, using microfluidics, nanomechanics and advanced optical techniques, to validate the various stages of the development of our models by targeting individual scales as well as interactions between scales. We will extend the first generation of models to study different modalities of existing and experimental therapeutic interventions for SCD, including simple transfusion, fetal hemoglobin (HbF) induction by hydroxyurea, and RBC hydration. Predictability of multiscale models requires quantifying uncertainty, and, to this end, we will incorporate polynomial chaos methods to model and propagate parametric uncertainties through the multiscale system. We plan to disseminate our models, software tools, and experimental data including the general-purpose triple-decker algorithm, via web-based repositories, existing public open-ware sites, tutorials and through the MSM consortium.

描述（由申请人提供）：本项目的目的是开发一种有效的多尺度建模方法，用于量化镰状细胞病（SCD）的生物物理特征-一种血液学疾病，影响美国数万人，每500名非洲裔美国人中就有一名出生时患有SCD的儿童。SCD的发病机制由以下原因引起：（1）由于红细胞（RBC）内的血红蛋白聚合而导致的不规则红细胞（RBC）形状;（2）RBC膜的硬化;以及（3）镰状RBC粘附到内皮和其他血细胞。这些现象的组合导致血管闭塞事件或“危象”，导致与SCD相关的大多数发病率和死亡率，但几乎不确定近端原因或其发生的环境。SCD血流和血管阻塞的精确建模所涉及的时空尺度跨越至少四个数量级，因此需要新的数值方法来模拟这种多尺度现象。我们提出了一种基于3D耗散粒子动力学（DPD）的通用方法来无缝地模拟流动和软物质，即，红细胞和其他血细胞，血浆，胞质溶胶，血红蛋白聚合和粘附动力学。DPD可以与分子动力学（MD）和基于三层算法的连续描述（例如Navier-Stokes）接口，我们已经开发了三层算法，以捕获分子细节或模拟大动脉或网络的计算效率。我们在这里采用了在我们以前的疟疾工作中证明非常有效的相同方法，即从全面的单细胞测量中获得信息和验证的单个RBC（健康或镰状）模型将用于预测SCD血流的集体动力学和流变学。我们还提出了一个系统的实验计划，使用微流体，纳米力学和先进的光学技术，通过针对单个尺度以及尺度之间的相互作用来验证我们模型发展的各个阶段。我们将扩展第一代模型，以研究SCD的现有和实验性治疗干预的不同模式，包括简单输血、通过羟基脲诱导胎儿血红蛋白（HbF）和RBC水合。多尺度模型的可预测性需要量化的不确定性，为此，我们将采用多项式混沌方法来建模和传播参数的不确定性通过多尺度系统。我们计划传播我们的模型，软件工具和实验数据，包括通用的三层算法，通过基于Web的存储库，现有的公共开放式网站，教程和通过MSM联盟。