Blood Systems Biology

血液系统生物学

• 批准号: 8134883
• 负责人: SCOTT L DIAMOND
• 金额: $ 75.01万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134883
• 关键词: Adhesions; Adhesives; Age; Aging; Agonist; Algorithms; Antibodies; Antiplatelet Drugs; Biological Assay; Biological Neural Networks; Biology; Biomedical Engineering; Blood; Blood Clot; Blood Platelets; Blood coagulation; Blood specimen; Calcium; Calibration; Clinical; Coagulation Process; Code; Collagen; Complex; Computer Simulation; Convection; Cytoplasmic Granules; Data; Data Set; Databases; Defect; Deposition; Development; Diamond; Diffusion; Disease; Epoprostenol; Epoprostenol Receptors; Ethnic Origin; Ethnic group; Event; F2R gene; Feedback; Female; Flow Cytometry; Gender Role; Genomics; Growth; Hematocrit procedure; Hemorrhage; Human; In Vitro; Individual; Integrins; Kinetics; Laser injury; Liquid substance; Maps; Measurement; Measures; Metabolic Pathway; Metabolism; Microfluidic Microchips; Microfluidics; Modeling; Monitor; Mus; Mutation; Neural Network Simulation; Operative Surgical Procedures; P-Selectin; PAWR gene; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Phosphatidylserines; Plasma; Platelet Activation; Probability; Production; Reaction; Research; Risk Assessment; Scanning; Signal Pathway; Signal Transduction; Simulate; Staging; Stenosis; Surface; Systems Biology; Testing; Thrombin; Thromboplastin; Thrombosis; Thromboxane Receptor; Thrombus; Time; Tracer; Training; Transgenic Mice; VWF gene; Validation; Venous; brass; clinically relevant; combinatorial; experience; hemodynamics; in vivo; inhibitor/antagonist; loss of function mutation; models and simulation; mouse model; public health relevance; receptor; release of sequestered calcium ion into cytoplasm; research study; response; simulation; stroke therapy; synergism; vector; web site

DESCRIPTION (provided by applicant): This proposal focuses on the integrative and high throughput functional phenotyping of human blood, matched by Systems Biology and Bioengineering approaches for patient-specific training of computer models to identify and quantify responses to clotting triggers or pharmacological agents. High throughput phenotyping of individual blood samples will be used to train bottom-up and top-down models of blood clotting under static, venous, and arterial hemodynamic conditions. Specific Aims are: Aim 1: Use high throughput intracellular calcium measurements to train neural network models to predict patient-specific response to combinatorial and sequential stimulation, thus testing the milieu that platelets actually experience during thrombosis. Furthermore, high throughput measures of inside-out signaling will be implemented for the development of large scale computational simulation of platelet metabolic pathways. Aim 2: Along with platelet phenotyping, we will use validated high throughput blood thrombin phenotyping to identify pathways and synergisms that are defective in patients with existing but undefined defects. These approaches then allow the development of a full platelet-plasma computer simulation of coagulation. Aim 3: Using validated tissue factor microarray-flow chambers and microfluidic chambers, we will functionally phenotype thrombus production and clot stability for normal donors and patients under hemodynamic conditions and pharmacological modulation. Aim 4: In vivo studies using a mouse laser injury model to follow evolving intrathrombic spatial gradients. The flow studies are supported by advanced multiscale Lattice Kinetic Monte Carlo (LKMC) simulation of clotting under flow using data from all three specific aims. These approaches represent the first full integration of platelet signaling models with realistic and hierarchical hemodynamic/mass transport simulations that regulate adhesive bond function and plasma protease networks. Better elucidation and quantitative measurement of blood reactions and platelet signaling pathways under hemodynamic conditions are directed at clinical needs in thrombosis risk assessment, anti-coagulation therapy during surgery, platelet targeted therapies, and stroke research. PUBLIC HEALTH RELEVANCE: Blood is ideal for Systems Biology research since it is easily obtained from donors or patients, amenable to high throughput liquid handling experiments, and clinically relevant. Clotting and bleeding diseases of aging are seldom due to acquired mutations and this drives the need for advanced functional phenotyping in concert with Systems Biology and other sequencing/genomic approaches.

描述（由申请人提供）：该提案着重于人类血液的综合和高吞吐量功能表型，与系统生物学和生物工程学方法相匹配，用于对计算机模型的患者特异性培训，以识别和量化对凝结触发器或药理剂的反应。在静态，静脉和动脉血液动力学条件下，单个血样的高通量表型将用于训练自下而上的血液凝结模型。具体目的是：目标1：使用高吞吐量细胞内钙测量值训练神经网络模型，以预测患者特异性对组合和顺序刺激的反应，从而测试血小板在血栓形成过程中实际经历的环境。此外，将实施高吞吐量的吞吐量测量，以开发血小板代谢途径的大规模计算模拟。 AIM 2：与血小板表型一起，我们将使用经过验证的高吞吐血凝血酶表型识别在现有但不确定缺陷的患者中有缺陷的途径和协同作用。然后，这些方法允许开发完整的血小板 - 等离子计算机模拟的凝结。 AIM 3：使用经过验证的组织因子微阵列 - 流室和微流体室，在血液动力学条件和药理调节下，我们将在功能上为正常供体和患者进行功能表型血栓产生和凝块稳定性。 AIM 4：使用小鼠激光损伤模型的体内研究遵循不断发展的肉眼空间梯度。流动研究由先进的多尺度晶格动力学蒙特卡洛（LKMC）模拟，使用来自所有三个特定目的的数据，对凝块下的凝结。这些方法代表了血小板信号传导模型的第一个完整整合，该模型具有逼真的和分层的血液动力/质量传输模拟，该模拟调节了粘合键功能和血浆蛋白酶网络。在血液动力学条件下，更好地阐明血液反应和血小板信号通路的定量测量是针对血栓形成风险评估，手术期间抗凝治疗，血小板靶向疗法和中风研究的临床需求。 公共卫生相关性：血液是系统生物学研究的理想选择，因为它很容易从供体或患者那里获得，可容纳高吞吐量液体处理实验，并且在临床上相关。由于获得的突变，很少有衰老的凝结和出血疾病，这驱动了与系统生物学和其他测序/基因组方法一起进行晚期功能表型的需求。