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

这个CAREER项目将开发新的数学模型和数值方法，用于模拟血液凝固和识别血液凝固系统中的调节机制。在血管损伤时，血液会凝结以防止出血。凝血反应是复杂的，并且涉及在流动的影响下一起工作的许多生物化学和生物物理组分。某些疾病或药物可能导致凝块形成不当，导致危及生命的出血或病理性凝块生长伴血管闭塞。由于凝血系统复杂的生物化学和生物物理学方面，预测其反应和确定这些反应的调控机制是困难的。血液凝固的数学模型为设计新药、实验和患者特异性治疗提供了强大的工具，但在制定此类模型方面仍存在巨大挑战。这项研究的重点是开发新的数学模型的基本生化球员和他们参与复杂的生物物理过程。这些模型将用于测试与血液凝固调节和最佳药物设计相关的假设。此外，研究生将接受跨学科研究的培训，并帮助组织数学生物学的夏季研讨会。这些研讨会将提供给当地社区学院的学生，目标是通过提供积极的学习，教师和研究生指导，同行网络和及时的建议，他们的招聘和保留到四年制课程。本研究将建立一个耦合血液凝固的生物化学、生物物理学和生物力学的综合建模框架。它将解决有关调节凝血过程中最重要的酶凝血酶的产生和隔离的机械问题。具体来说，研究将集中在（1）开发一个数学模型，准确地描述凝血酶的结合纤维蛋白（稳定生长的血凝块的聚合物）并解释了凝血酶在流动下保持与纤维蛋白结合的延长的时间段，（2）开发了一种数学模型，该模型结合了一种新的，血小板依赖性机制抑制凝血酶生成，并解释了在流动下观察到的抑制，以及（3）开发了一种新的数值方法，将血小板建模为浸入流体中的离散物体，弹性相互作用，该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.