Overview

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 Penn Blood Systems Biology Cluster will develop a unified working model of blood as a reactive biological fluid, a multicellular “organ” whose function is dictated by prevailing hemodynamics, endogenous platelets, and plasma protein states. The projects of the Cluster progress from early platelet adhesion events to coagulation and thrombus build-up to clot retraction, stability, and embolism.

A Systems Biology approach enhances understanding of drug-drug interactions and drug mechanisms of action, as well as assessment of the relative contributions of numerous interconnecting pathways during thrombosis.  With a focus on platelets and plasma, these approaches will be validated into a hierarchical computational/experimental platform to address issues of blood pathogenesis and therapy.  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. detection of platelet function in formed thrombi and testing of intracellular signaling models for platelets under realistic hemodynamic conditions.

Lead Project (Scott. L. Diamond, Lead PI)

The lead project 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.

Project  (Michael King Univ. Rochester/D. A. Hammer, Collaborating PIs)

This project 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 alphaIIb-beta3 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.

Project (Skip Brass, Collaborating PI)

Specific Aim 3 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.