Blood Systems Biology

描述（由申请人提供）： 宾夕法尼亚大学响应RFA-HL-06-004，组建了一支由工程与应用科学学院和医学院的教师组成的跨学科团队，他们具有实验和计算血液动力学，键力学和生物流变学，运输物理学，血小板生物学，凝血和蛋白酶生物化学，连续/随机模拟，逆问题，和基因敲除小鼠用于血栓形成研究。集群团队将部署综合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类血液的时空过程。为3个群组项目确定了具体目标：具体目标1（项目一：D. A. Hammer，合作PI）将专注于血小板流体动力学和受体结合和信号传导（GPIb/vWF和GPVI/胶原蛋白），由外向内/由内而外的信号传导导致α 2 β 1和β 2 β 1-β S活化。血小板粘附动力学模拟血小板捕获、滚动、活化、阻滞和栓塞作为流体剪切速率的函数，将与使用平行板流动室的实验进行比较。具体目标2（项目二：S。L. Diamond，铅PI）将专注于模拟和实验的血小板沉积在反应性表面上的存在下，凝血流动条件。将激动剂活化、血小板沉积/碎裂、颗粒释放和凝血酶生成的动力学Monte Carlo/Continuum模拟与在孔板、锥板粘度计和平行板流动池中运行的实验进行比较。具体目标3（项目三：L. F.黄铜，合作PI）将集中在凝血酶受体功能和血小板-血小板相互作用内形成的聚集体有关的信号传导，凝块稳定性和收缩。人血和正常及基因敲除小鼠血将用于原位检测形成血栓中的血小板功能，并在实际血液动力学条件下测试血小板的细胞内信号传导模型。非专业人士声明：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，适合高通量液体处理实验，并且具有临床相关性。更好地阐明和定量模拟血液反应和血液动力学条件下的血小板信号传导途径是针对血栓形成风险评估，抗凝治疗，血小板靶向治疗和中风研究的临床需求。

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.