In response to PAR-12-138, this proposal focuses on the integrative and high throughput functional phenotyping of human blood, matched by Systems Biology and Bioengineering approaches for patient-specific training of computer models to identify and quantify responses to clotting triggers or pharmacological agents. A multi-investigator team of bioengineers, computational scientists, radiologists, and hematologists at the University of Pennsylvania and UC-Berkeley will investigate human platelet genetics and signaling, blood coagulation proteases, and blood biochemistry in the hierarchical context of clotting under complex hemodynamic conditions.
Four specific aims are:
Aim 1 explores the transition from regulated hemostasis to thrombosis to embolism with emphasis on platelet contractile forces, fibrin formation, and von Willebrand Factor unfolding. Experiments and model building will include contact pathway activation and its triggers, relevant to in vitro diagnostics and potentially anti-thrombotic therapies. Computer simulations are focused at the molecular, cellular, and local coronary artery scale, including data-driven models derived using blood parameters derived from healthy individuals.
Aim 2 will focus on simulation of acute myocardial infarction (aMI) using patient-specific platelet/coagulation models and the patient's own complete coronary anatomy obtained by CT-angiography. Then, a large in silico patient cohort will be created to score aMI severity metrics to identify multidimensional risk factors and drug efficacy.
Aim 3 will utilize an arterial mouse laser injury model of arterial thrombosis to create n vivo data sets of intraclot transport and reaction, thus providing an in vivo setting for testing Systems Biology predictions. The in vivo work will emphasize the use of novel fluorescent sensors developed specifically for this research. Overall, these approaches represent the full integration of platelet signaling models with realistic and hierarchical hemodynamic/mass transport simulations that regulate adhesive bond function and plasma protease networks. Better elucidation and quantitative measurement of blood reactions and platelet signaling pathways under hemodynamic conditions are directed at clinical needs in thrombotic risk assessment, safer and more focused anti-coagulant or anti-platelet therapies, and stroke research.
Blood is ideal for Systems Biology research since it is easily obtained from donors or patients, amenable to high throughput liquid handling or microfluidic experiments, and clinically relevant. Clotting and bleeding diseases of aging are seldom due to acquired mutations and this drives the need for advanced functional phenotyping in concert with Systems Biology and other sequencing/genomic approaches. The overall goal is full simulation of a heart attack using a patient's own coronary geometry, hemodynamics, and unique blood biology so as to better stratify patient risk and create safer treatments.
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