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

这个职业项目将开发新的数学模型和数值方法，用于模拟血液凝结和识别血液凝结系统内的调节机制。血管损伤后，血液会凝结以防止出血。凝血反应是复杂的，涉及许多生化和生物物理成分在流动的影响下协同工作。某些疾病或药物可能会导致血栓不正确地形成，导致危及生命的出血或血管闭塞的病理性血栓生长。由于凝血系统复杂的生化和生物物理方面，预测其反应和确定这些反应背后的调节机制是困难的。凝血的数学模型为设计新药、实验和针对患者的治疗提供了强大的工具，但在建立这样的模型方面仍然存在巨大的挑战。这项研究的重点是开发基本生化参与者的新数学模型，以及他们参与复杂的生物物理过程。这些模型将被用来检验与血液凝结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方面的培训，并帮助组织数学生物学的暑期研讨会。这些研讨会将面向当地社区大学的学生，目标是通过提供积极的学习、教师和研究生指导、同伴网络和及时的建议，招募和保留他们进入四年制项目。这项研究将建立一个全面的建模框架，将血液凝固的生物化学、生物物理和生物力学结合在一起。它将解决有关调节凝血酶的生成和隔离的机制问题，凝血酶是凝血过程中最重要的酶。具体地说，研究将集中于(1)发展准确描述凝血酶与纤维蛋白(稳定增长的血液凝块的聚合物)的结合的数学模型，并解释观察到的凝血酶在流动状态下与纤维蛋白结合的延长时间，(2)发展结合了抑制凝血酶生成的新的依赖于血小板的机制并解释流动条件下观察到的抑制的数学模型，以及(3)发展一种新的数值方法，将血小板模拟为浸入流体中的离散物体，弹性地相互作用，对周围流体中的分子作出反应，这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.