CAREER: Mathematical Modeling to Identify New Regulatory Mechanisms of Blood Clotting

This CAREER project will develop new mathematical models and numerical methods for simulating blood clotting and identifying regulatory mechanisms within the blood clotting system. In response to vessel injuries, blood will clot to prevent bleeding. The clotting response is complex and involves numerous biochemical and biophysical components working together under the influence of flow. Certain diseases or drugs may cause clots to form improperly, resulting in life-threatening bleeding or pathological clot growth with vessel occlusion. Due to the intricate biochemical and biophysical aspects of the clotting system, predicting its responses and identifying the regulatory mechanisms underlying these responses is difficult. Mathematical models of blood clotting provide powerful tools for designing new drugs, experiments, and patient-specific therapies, but there are still great challenges in formulating such models. This research focuses on developing new mathematical models of essential biochemical players and their involvement in complex biophysical processes. These models will be used to test hypotheses related to regulation of blood clotting and optimal drug design. Additionally, graduate students will be trained in interdisciplinary research and help to organize summer workshops in mathematical biology. The workshops will be offered to local community college students, with the goal being their recruitment and retention into four-year programs by offering active learning, faculty and graduate student mentoring, peer networking, and timely advising. This research will build a comprehensive modeling framework coupling the biochemistry, biophysics, and biomechanics of blood clotting. It will address mechanistic questions about regulating the generation and sequestration of thrombin, the most important enzyme in the clotting process. Specifically, the research will focus on (1) development of a mathematical model that accurately describes thrombin's binding to fibrin (the polymer that stabilizes growing blood clots) and explains the extended periods of time that thrombin has been observed to stay bound to fibrin under flow, (2) development of a mathematical model that incorporates a new, platelet-dependent mechanism to inhibit thrombin generation and explains observed inhibition under flow, and (3) development of a new numerical method to model platelets as discrete objects immersed in a fluid, interacting elastically, responding to molecules in the surrounding fluid, and carrying information via molecules bound to their surfaces. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.