Blood Systems Biology

血液系统生物学

基本信息

批准号：
8927743
负责人：
SCOTT L DIAMOND
金额：
$ 76.18万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8927743
关键词：
Acute Acute myocardial infarction Adhesives Aging Agonist Albumins Algorithms Anatomy Angiography Animal Model Binding Biochemistry Biocompatible Materials Biological Biological Assay Biological Neural Networks Biology Biomedical Engineering Blood Blood Platelets Blood coagulation Blood specimen Calcium Cardiac Clinical Coagulants Coagulation Process Code Complex Computer Simulation Coronary Coronary artery Cytometry DNA Data Data Set Defect Deposition Development Diagnostic Diamond Differential Equation Diffusion Disease Distal Embolism Event Exercise Extravasation Factor XIIa Fiber Fibrin Fibrinogen Genetic Genomic approach Geometry Goals Growth Heart Hematologist Hematology Hemorrhage Hemostatic Agents Hemostatic function Human Hyperactive behavior In Vitro Individual Infarction Kaolin Kinetics Laser injury Link Liquid substance Low-Density Lipoproteins Measurement Measures Mechanics Microfluidic Microchips Microfluidics Modeling Molecular Mus Mutation Myocardial Infarction Outpatients P-Selectin Pathway interactions Patient risk Patients Pennsylvania Peptide Hydrolases Permeability Phase Phenotype Plasma Platelet Activation RNA Radiology Specialty Reaction Recruitment Activity Research Research Personnel Rest Risk Risk Assessment Risk Factors Role Running Rupture Scanning Scientist Severities Signal Pathway Signal Transduction Stenosis Stress Tests Systems Biology Testing Thrombin Thrombosis Thrombus Training Transport Reaction Universities VWF gene Whole Blood Work X-Ray Computed Tomography Zea mays trypsin inhibitor blebbistatin brass clinically relevant cohort drug efficacy experience hemodynamics high risk high throughput screening in vivo in vivo Model inhibitor/antagonist model building mouse model novel particle polymerization pressure public health relevance radiologist research study response risk minimization sensor simulation solute spatiotemporal stroke therapy von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): In response to PAR-12-138, 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. A multi-investigator team of bioengineers, computational scientists, radiologists, and hematologists at the University of Pennsylvania and UC-Berkeley will investigate human platelet genetics and signaling, blood coagulation proteases, and blood biochemistry in the hierarchical context of clotting under complex hemodynamic conditions. Four specific aims are: Aim 1 explores the transition from regulated hemostasis to thrombosis to embolism with emphasis on platelet contractile forces, fibrin formation, and von Willebrand Factor unfolding. Experiments and model building will include contact pathway activation and its triggers, relevant to in vitro diagnostics and potentially anti-thrombotic therapies. Computer simulations are focused at the molecular, cellular, and local coronary artery scale, including data-driven models derived using blood parameters derived from healthy individuals. Aim 2 will focus on simulation of acute myocardial infarction (aMI) using patient-specific platelet/coagulation models and the patient's own complete coronary anatomy obtained by CT-angiography. Then, a large in silico patient cohort will be created to score aMI severity metrics to identify multidimensional risk factors and drug efficacy. Aim 3 will utilize an arterial mouse laser injury model of arterial thrombosis to create n vivo data sets of intraclot transport and reaction, thus providing an in vivo setting for testing Systems Biology predictions. The in vivo work will emphasize the use of novel fluorescent sensors developed specifically for this research. Overall, these approaches represent the 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 thrombotic risk assessment, safer and more focused anti-coagulant or anti-platelet therapies, and stroke research.

描述（由应用程序提供）：响应PAR-12-138，该提案着重于人类血液的综合且高吞吐量的功能表型，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，以识别和量化对服装触发器或药品药物的反应。宾夕法尼亚大学和UC-Berkeley的生物工程，计算科学家，放射科学家和血液学家组成的多次投诉团队将调查在复杂的血液动力学的服装等级服装中，人类的血小板遗传学和信号传导，血液凝结蛋白酶以及血液凝结蛋白酶以及血液生物化学。四个具体目的是：AIM 1探讨了从调节的止血到血栓形成到栓塞的过渡，重点是血小板收缩力，纤维蛋白形成和von Willebrand因子展开。实验和模型构建将包括与体外诊断有关的接触途径激活及其触发器以及潜在的抗脉止性疗法。计算机模拟集中在分子，细胞和局部冠状动脉量表上，包括使用来自健康个体的血液参数得出的数据驱动模型。 AIM 2将专注于使用患者特异性血小板/凝结模型以及通过CT血管造影获得的患者自身完全的冠状动脉解剖结构来模拟急性心肌梗塞（AMI）。然后，将创建一个大型计算机患者队列以评分AMI严重性指标，以识别多维风险因素和药物效率。 AIM 3将利用伪像的伪像模型来创建n个体内插槽传输和反应的体内数据集，从而为测试系统生物学预测提供了体内设置。体内工作将强调专门为这项研究开发的新型荧光传感器的使用。总体而言，这些方法代表了血小板信号模型与逼真和分层的血液动力/质量传输模拟的完整整合，这些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，更安全，更集中的抗凝蛋白或抗血域疗法的临床需求，以及中风研究。