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: 2341362
• 负责人: Karin Leiderman
• 金额: $ 51万
• 依托单位: University of North Carolina at Chapel Hill
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2341362&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.

该职业项目将开发新的数学模型和数值方法，以模拟血液凝结并识别血液凝结系统中的调节机制。为了应对血管受伤，血液会凝结以防止出血。凝血反应很复杂，涉及在流动影响下共同工作的许多生化和生物物理成分。某些疾病或药物可能会导致凝块形成不当，从而导致危及生命的出血或血管闭塞病理凝块生长。由于凝结系统的复杂生化和生物物理方面，很难预测其反应并确定这些反应的调节机制。血凝结的数学模型为设计新药，实验和患者特异性疗法提供了强大的工具，但是在制定此类模型方面仍然存在巨大挑战。这项研究重点是开发基本生化参与者的新数学模型及其参与复杂的生物物理过程。这些模型将用于测试与血液凝结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，并有助于组织数学生物学的夏季研讨会。讲习班将提供给当地社区大学生，其目标是通过提供积极学习，教职员工和研究生指导，同伴网络以及及时的建议，招募和保留为四年计划。这项研究将建立一个综合建模框架，结合血液凝结的生物化学，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。 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）开发一种新的数值方法，将血小板建模为浸入流体中的离散物体，弹性相互作用，对周围流体中的分子做出响应，并通过分子携带的信息与其表面绑定。该奖项反映了NSF的法定任务，并通过评估了CRETURITAIL MERITAIL MERIAL和BRODIT和BRODIT和BRODIT，并通过评估了支持。