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 #
5R33HL087385-02
Application #
7291558
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
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$305,865
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Welsh, J D; Colace, T V; Muthard, R W et al. (2012) Platelet-targeting sensor reveals thrombin gradients within blood clots forming in microfluidic assays and in mouse. J Thromb Haemost 10:2344-53
Stalker, Timothy J; Newman, Debra K; Ma, Peisong et al. (2012) Platelet signaling. Handb Exp Pharmacol :59-85
Signarvic, Rachel S; Cierniewska, Aleksandra; Stalker, Timothy J et al. (2010) RGS/Gi2alpha interactions modulate platelet accumulation and thrombus formation at sites of vascular injury. Blood 116:6092-100
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
Wannemacher, Kenneth M; Zhu, Li; Jiang, Hong et al. (2010) Diminished contact-dependent reinforcement of Syk activation underlies impaired thrombus growth in mice lacking Semaphorin 4D. Blood 116:5707-15
Zhu, Li; Stalker, Timothy J; Fong, Karen P et al. (2009) Disruption of SEMA4D ameliorates platelet hypersensitivity in dyslipidemia and confers protection against the development of atherosclerosis. Arterioscler Thromb Vasc Biol 29:1039-45