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）：该项目的目的是开发一种经过验证的多尺度建模方法，用于量化镰状细胞病（SCD）的生物物理特征（SCD） - 一种血液学疾病，会影响我们中成千上万的人，每500名非裔美国人出生，导致儿童患有SCD。 SCD的发病机理是由（1）由于RBC内部血红蛋白聚合引起的（1）不规则的红细胞（RBC）形状。（2）加速膜的僵硬；（3）镰状RBC粘附在内皮和其他血细胞上。这些现象的结合导致血管占地事件或造成与SCD相关的大多数发病率和死亡率的“危机”，但对近端原因或发生的情况很少。与准确建模SCD血流和血管咬合跨度至少四个数量级的时空尺度，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耗散颗粒动力学（DPD）的一般方法，以无缝地模型，即RBC和其他血细胞，血浆，细胞质，血红蛋白聚合和粘附动力学。 DPD可以与分子动力学（MD）相连，并基于基于连续性的描述（例如Navier-Stokes）基于我们开发的三甲基算法，以捕获分子细节或分别模拟大型动脉或网络的计算效率。我们在这里采用了相同的方法，这些方法已证明在我们先前的疟疾工作中非常有效，即单一RBC（健康或谨慎）的模型，通过全面的单细胞测量值进行了知情和验证，将用于预测SCD血流的集体动态和流变学。我们还使用微流体，纳米力学和高级光学技术提出了系统的实验计划，通过靶向单个尺度以及量表之间的相互作用来验证模型开发的各个阶段。我们将扩展第一代模型，以研究SCD现有和实验性治疗干预措施的不同方式，包括简单输血，羟基脲和RBC水合的胎儿血红蛋白（HBF）诱导。多尺度模型的可预测性需要量化不确定性，为此，我们将结合多项式混乱方法，以通过多尺度系统对参数不确定性进行建模和传播。我们计划通过基于Web的存储库，现有的公共开放软件网站，教程和MSM联盟来传播我们的模型，软件工具和实验数据，包括通用三重甲板算法。