Blood Systems Biology

血液系统生物学

基本信息

批准号：
7487304
负责人：
SCOTT L DIAMOND
金额：
$ 31.19万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-29 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7487304
关键词：
3-Dimensional ADP Receptors Address Adhesions Adhesives Agonist Algorithms Antithrombins Appendix Applied Research Area Binding Biochemical Biochemistry Bioinformatics Biological Biological Assay Biology Biomechanics Biomedical Engineering Blood Blood Platelets Blood Vessels Blood coagulation Blood flow Calcium Cell Shape Cell Size Cells Cereals Chemicals Chemistry Clinical Clot retraction Coagulation Process Code Collagen Communication Communities Community Outreach Complement Complex Computer Simulation Computer software Condition Consensus Consultations Convection Coupled Couples Cytoplasmic Granules Data Data Set Database Management Systems Databases Deposition Detection Development Development Plans Devices Diagnostic Diamond Diffusion Disease regression Drug Interactions Embolism Endopeptidases Endothelium Engineering Epinephrine Epoprostenol Equilibrium Evaluation Event Experimental Designs Experimental Models Exposure to F2R gene Factor VIII-Related Antigen Factor Xa Faculty Fibrin Fibrinogen Fibrinogen Receptors Fibrinolysis Figs - dietary Floor Fluorescent Antibody Technique Frequencies Funding Future G Protein-Coupled Receptor Genes Generations Goals Head Hemostatic function Human Image In Situ In Vitro Individual Integrins International Kaolin Kinetics Knockout Mice Label Language Lead Length Ligand Binding Ligands Liquid substance Maps Measurement Measures Mechanics Mediating Metabolism Methods Microscopic Microscopy Modeling Molecular Monitor Monoclonal Antibodies Motion Mus Names Object Attachment Organ Output PAC1 phosphatase Pathogenesis Pathway interactions Patients Pennsylvania Peptide Hydrolases Peptides Perfusion Pharmaceutical Preparations Photons Physics Plasma Plasma Proteins Platelet Activation Population Predisposition Principal Investigator Printing Probability Process Production Proteins Prothrombin Publications Range Rate Reaction Reagent Relative (related person)Research Research Personnel Resolution Resources Retinal Cone Risk Assessment Role Running Schedule Schools Signal Pathway Signal Transduction Simulate Societies Speed Structure Surface Suspension substance Suspensions Systems Biology TFPI TRAP Peptide Testing Theoretical Studies Thrombin Thrombin Receptor Thromboplastin Thrombosis Thromboxanes Thrombus Time TimeLine Tracer United States National Institutes of Health Universities Update VWF gene Validation Whole Blood Work activated Protein C analog antithrombin III-protease complex base brass clinically relevant cohesion combinatorial convulxin design drug mechanism experience fibrinopeptide hemodynamics high throughput screening inhibitor/antagonist medical schools member model development molecular scale monomer network models neutrophil novel outreach phosphoric diester hydrolase programs receptor receptor function research study response shear stress simulation single bond size small molecule libraries spatial integration stroke therapy surface coating symposium tool von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): The University of Pennsylvania, in response to RFA-HL-06-004, has assembled an interdisciplinary team of faculty from the School of Engineering and Applied Sciences and the School of Medicine with expertise in experimental and computational hemodynamics, bond mechanics and biorheology, transport physics, platelet biology, coagulation and protease biochemistry, continuum/stochastic simulation, inverse problems, and knockout mice for thrombosis research. The Cluster Team will deploy integrative and hierarchical computational models and experimental studies to predict spatial-temporal processes in mouse and human blood under hemodynamic conditions. Specific Aims are defined for 3 Cluster projects: Specific Aim 1 (Project I: D. A. Hammer, Collaborating PI) will focus on platelet hydrodynamics and receptor bonding and signaling (GPIb/vWF and GPVI/collagen) with outside-in/inside-out signaling leading to alpha2beta1 and alphallb-betaS activation. Platelet Adhesive Dynamics simulation of platelet capture, rolling, activation, arrest, and embolism as a function of fluid shear rate will be compared to experiment using parallel-plate flow chambers. Specific Aim 2 (Project II: S. L. Diamond, Lead PI) will focus on simulation and experiment of platelet deposition on a reactive surface in the presence of coagulation under flow conditions. Kinetic Monte Carlo/Continuum simulation of agonist activation, platelet deposition/fragmentation, granule release, and thrombin generation will be compared to experiments run in well plates, cone-and-plate viscometer, and parallel-plate flow cells. Specific Aim 3 (Project III: L. F. Brass, Collaborating PI) will focus on thrombin receptor function and platelet- platelet interactions within formed aggregates relating to signaling, clot stability, and retraction. Both human blood and normal and knockout mouse blood will be used for in situ detection of platelet function in formed thrombi and testing of intracellular signaling models for platelets under realistic hemodynamic conditions. Lay Statement: 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. Better elucidation and quantitative simulation of blood reactions and platelet signaling pathways under hemodynamic conditions are directed at clinical needs in thrombosis risk assessment, anti-coagulation therapy, platelet targeted therapies, and stroke research.

描述（由申请人提供）：宾夕法尼亚大学的RFA-HL-06-004响应于工程和应用科学学院和医学学院的跨学科团队，并具有实验和计算血液动力学，邦德和生物学，运输物理学，血小板生物学，促进和蛋白质的综合和蛋白质，综合综合体，综合综合体，综合综合综合综合综合综合综合综合综合综合体，邦德和生物学方面的专业知识敲除小鼠进行血栓形成研究。集群团队将部署整合性和分层计算模型和实验研究，以预测血液动力学条件下小鼠和人体血液中的时空过程。为3个集群项目定义了具体目的：具体目标1（项目I：D。A. Hammer，合作PI）将重点放在血小板流体动力学以及受体键合和信号传导（GPIB/VWF和GPVI/GPVI/胶原蛋白）上，并带有外部/内外信号传导，导致Alpha2beta1和Alphalphalb-betas-betas-betas-betas激活。血小板粘合剂动力学模拟了血小板捕获，滚动，激活，停滞和栓塞作为流体剪切速率的函数的函数，将与使用平行板流室的实验进行比较。特定的目标2（项目II：S。L. Diamond，Lead PI）将集中于在流动条件下存在凝结的情况下在反应性表面上的血小板沉积的模拟和实验。动力学激活，血小板沉积/碎片化，颗粒释放和凝血酶生成的动力学蒙特卡洛/连续模拟与在井板，锥形和板粘膜和平行板流动细胞中进行的实验将进行比较。具体目标3（项目III：L。F. Brass，协作PI）将重点关注与信号，凝块稳定性和缩回有关的组成骨料中的凝血酶受体功能和血小板 - 血小板相互作用。人体血液和正常小鼠血液都将用于原位检测形成的血栓形成的血小板功能，并在逼真的血液动力学条件下测试血小板的细胞内信号传导模型。外行陈述：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，可与高吞吐量液体处理实验以及临床相关。血液动力学条件下的血液反应和血小板信号通路的更好阐明和定量模拟针对血栓形成风险评估，抗癌疗法，血小板靶向疗法和中风研究的临床需求。