? 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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
1R33HL087317-01
Application #
7209536
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Program Officer
Qasba, Pankaj
Project Start
2006-09-29
Project End
2009-07-31
Budget Start
2006-09-29
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$310,173
Indirect Cost
Name
University of Pennsylvania
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lee, Dooyoung; Fong, Karen P; King, Michael R et al. (2012) Differential dynamics of platelet contact and spreading. Biophys J 102:472-82
Flamm, Matthew H; Sinno, Talid; Diamond, Scott L (2011) Simulation of aggregating particles in complex flows by the lattice kinetic Monte Carlo method. J Chem Phys 134:034905
Diamond, Scott L (2010) Tissue factor activity under flow. Thromb Res 125 Suppl 1:S29-30
Chatterjee, Manash S; Purvis, Jeremy E; Brass, Lawrence F et al. (2010) Pairwise agonist scanning predicts cellular signaling responses to combinatorial stimuli. Nat Biotechnol 28:727-32
Chatterjee, Manash S; Denney, William S; Jing, Huiyan et al. (2010) Systems biology of coagulation initiation: kinetics of thrombin generation in resting and activated human blood. PLoS Comput Biol 6:
Maloney, S F; Brass, Lawrence F; Diamond, S L (2010) P2Y12 or P2Y1 inhibitors reduce platelet deposition in a microfluidic model of thrombosis while apyrase lacks efficacy under flow conditions. Integr Biol (Camb) 2:183-92
Purvis, Jeremy E; Radhakrishnan, Ravi; Diamond, Scott L (2009) Steady-state kinetic modeling constrains cellular resting states and dynamic behavior. PLoS Comput Biol 5:e1000298
Flamm, Matthew H; Diamond, Scott L; Sinno, Talid (2009) Lattice kinetic Monte Carlo simulations of convective-diffusive systems. J Chem Phys 130:094904
Diamond, S L (2009) Systems biology to predict blood function. J Thromb Haemost 7 Suppl 1:177-80
Stalker, T J; Wu, J; Morgans, A et al. (2009) Endothelial cell specific adhesion molecule (ESAM) localizes to platelet-platelet contacts and regulates thrombus formation in vivo. J Thromb Haemost 7:1886-96

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