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，他们在实验和计算血流动力学、键合力学和生物流变学、传输物理、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方面具有专业知识，用于血栓研究。集群团队将部署综合和分级计算模型和实验研究，以预测血流动力学条件下小鼠和人类血液的时空过程。为3个集群项目定义了具体目标：特定目标1(项目I：D.A.Hammer，协作PI)将专注于血小板流体动力学和受体结合和信号转导(GPIB/vWF和GPVI/胶原)，以及由外到内/由内向外的信号转导导致α2beta1和Alphallb-Betas激活。血小板黏附动力学模拟血小板捕获、滚动、激活、停滞和栓塞作为流体剪切率的函数，将与使用平行平板流室的实验进行比较。具体目标2(项目II：S·L·钻石，铅PI)将侧重于在流动条件下凝聚存在的情况下，血小板在反应表面沉积的模拟和实验。激动剂激活、血小板沉积/碎裂、颗粒释放和凝血酶生成的动力学蒙特卡罗/Continuum模拟将与在井板、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III：L.F.黄铜，合作PI)将侧重于凝血酶受体功能和与信号、凝块稳定性和回缩相关的已形成聚集体内的血小板-血小板相互作用。人类血液和正常和基因敲除的小鼠血液将用于原位检测血栓形成中的血小板功能，并在现实的血液动力学条件下测试血小板的细胞内信号模型。LAY声明：血液是系统生物学研究的理想选择，因为它很容易从捐献者或患者那里获得，易于接受高通量液体处理实验，并且具有临床意义。更好地阐明和定量模拟血液动力学条件下的血液反应和血小板信号通路，旨在满足血栓形成风险评估、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): Title: Blood Systems Biology 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.