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

职业：通过数学模型确定新的凝血调节机制

• 批准号: 1848221
• 负责人: Karin Leiderman
• 金额: $ 51万
• 依托单位: Colorado School of Mines
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1848221&HistoricalAwards=false
• 关键词: CAREER; Mathematical; Modeling; Identify; New

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.

这个职业项目将开发新的数学模型和数值方法来模拟血液凝固和确定血液凝固系统中的调节机制。当血管受伤时，血液会凝结以防止出血。凝血反应是复杂的，涉及许多生物化学和生物物理成分在血流的影响下共同工作。某些疾病或药物可能导致凝块不正确形成，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化和生物物理方面，预测其反应并确定这些反应背后的调节机制是困难的。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，但在制定这些模型方面仍然存在巨大的挑战。本研究的重点是发展新的数学模型的基本生化参与者和他们参与复杂的生物物理过程。这些模型将用于测试与凝血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夏季讲习班。这些研讨会将面向当地社区大学的学生，目标是通过提供主动学习、教师和研究生指导、同伴网络和及时的建议，将他们招募并保留到四年的课程中。本研究将建立一个综合的模型框架，结合血液凝固的生物化学、生物物理学和生物力学。它将解决有关调节凝血酶的产生和隔离的机制问题，凝血酶是凝血过程中最重要的酶。具体来说，研究将集中在(1)建立一个数学模型，准确描述凝血酶与纤维蛋白（稳定生长的血栓的聚合物）的结合，并解释凝血酶在流动中与纤维蛋白结合的时间延长；(2)建立一个数学模型，结合一种新的血小板依赖机制来抑制凝血酶的产生，并解释在流动中观察到的抑制作用。(3)发展了一种新的数值方法，将血小板作为浸入流体中的离散物体，进行弹性相互作用，对周围流体中的分子作出反应，并通过与其表面结合的分子携带信息。该奖项反映了美国国家科学基金会的法定使命，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。

项目成果

Mathematical models of fibrin polymerization: past, present, and future

纤维蛋白聚合的数学模型：过去、现在和未来

• DOI: 10.1016/j.cobme.2021.100350
• 发表时间: 2021
• 期刊: Current Opinion in Biomedical Engineering
• 影响因子: 3.9
• 作者: Nelson, Anna C.;Kelley, Michael A.;Haynes, Laura M.;Leiderman, Karin
• 通讯作者: Leiderman, Karin

A Mathematical Model of Bivalent Binding Suggests Physical Trapping of Thrombin within Fibrin Fibers

• DOI: 10.1016/j.bpj.2019.09.003
• 发表时间: 2019-10-15
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Kelley, Michael;Leiderman, Karin
• 通讯作者: Leiderman, Karin