Blood Systems Biology
Principal Investigator: L Brass
Abstract: [unreadable] 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. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-09-29 - 2010-07-31
more information: NIH RePORT
- Disruption of SEMA4D ameliorates platelet hypersensitivity in dyslipidemia and confers protection against the development of atherosclerosisLi Zhu
Department of Medicine and Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA
Arterioscler Thromb Vasc Biol 29:1039-45. 2009..Here we tested the hypothesis that deleting sema4D will attenuate the adverse consequences of dyslipidemia on platelets and the vessel wall...
- Diminished contact-dependent reinforcement of Syk activation underlies impaired thrombus growth in mice lacking Semaphorin 4DKENNETH M WANNEMACHER
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Blood 116:5707-15. 2010..These 2 processes are interdependent, but distinguishable...
- RGS/Gi2alpha interactions modulate platelet accumulation and thrombus formation at sites of vascular injuryRachel S Signarvic
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Blood 116:6092-100. 2010....