CAREER: An integrated research and education program on the biomechanics of blood clot growth

1351672 Neeves血凝块构成了一个精巧的工程系统，其中复杂的流体在受伤部位转化为固体栓塞。 稳定的止血凝块设计用于止血而不堵塞血管，承受血液流动的力量，并随着伤口愈合过程缓慢溶解。任何这些事件的不稳定性都可能导致过度凝血或血栓形成，这是死亡的主要原因。 尽管在血凝块形成的生物化学和细胞生物学方面有广泛的知识基础，但止血血凝块和血栓性血凝块之间的机制差异在很大程度上仍然未知。来自PI实验室和其他实验室的最新发现表明，阻碍溶质从凝块核心转运是可能预防血栓形成的一种机制。 基于这一证据，拟定研究的假设是凝血因子和血小板激动剂在血细胞间质内的转运是凝块生长的关键调节因子。 如果这一假设被证明是正确的，那么针对这一生物物理机制与传统的生化机制相结合，可能会导致更有效的治疗血栓形成。智力优点：这一建议调查了一个重要的生理系统，通过发展之间的定量关系凝块组成和增长。凝块形成的传统模型主要集中在凝血反应和血小板信号传导中涉及的动力学过程。 拟议的研究建立在以前的模型，将间质溶质转运作为凝块生长的关键机制。 有了更有能力的预测方法，可以开发更好的药物和药物递送策略。 这一假设将通过以下具体目标来解决：（i）确定调节凝块生长和停滞的转运屏障，（ii）绘制凝块的孔结构，以及（iii）利用间质转运来调节凝块生长。所实施的方法依赖于应用多孔介质传输领域的理论和方法来表征组织中的传输。 血管损伤的体外和体内模型将用于测量凝块中的转运特性及其间质孔隙空间的结构。 将开发一系列生理条件下的本构关系，描述溶质转运作为凝块结构和组成的函数。 结果将用于评估已知的血栓形成风险因素如何导致不受控制的凝块生长，以及如何在物理上阻碍这一过程。更广泛的影响：拟议的研究将开发理论和实验模型，以预测血凝块生长和测试新的治疗策略。 这是一个潜在的变革性结果，因为控制血栓形成是医学上的重大挑战之一。该研究计划通过创建K-12外展计划和本科生研究机会与教育计划相结合，重点是工程和生物学之间的接口。 具体的教育和推广目标包括：（一）通过实践课程改善中学生对科学的态度，（二）在一所以拉丁裔学生为主的高中制定和评估生物工程方面的探究式学习计划，以及（iii）与科罗拉多儿童医院合作，为多元文化工程项目的学生建立细胞生物力学的暑期本科生研究项目在科罗拉多矿业学校

1351672NeevesBlood clots constitute an exquisitely engineered system, in which a complex fluid transforms into a solid plug at the site of an injury. Stable hemostatic clots are designed to arrest bleeding without occluding the vessel, withstand the forces of flowing blood, and slowly dissolve in concert with the wound healing process. Instabilities in any of these events can cause excessive clotting, or thrombosis, which is a leading cause of death. Despite the extensive knowledge base on the biochemistry and cell biology of clot formation, the mechanistic differences between a hemostatic clot and a thrombotic one remain largely unknown. Recent findings from the laboratory of the PI and from other labs suggest that impeding the transport of solutes away from the core of a clot is one mechanism that may prevent thrombosis. Based on this evidence, the hypothesis of the proposed studies is that transport of coagulation factors and platelet agonists within the interstitial space between blood cells is a key regulator of clot growth. If this hypothesis proves correct, then targeting this biophysical mechanism in conjunction with the conventional biochemical mechanisms could lead to more effective treatment of thrombosis.Intellectual Merit:This proposal investigates an important physiological system through the development of quantitative relationships between clot composition and growth. The conventional models of clot formation focus primarily on the kinetic processes involved in coagulation reactions and platelet signaling. The proposed studies build upon previous models by incorporating interstitial solute transport as a key mechanism of clot growth. With more capable predictive methods available, better drugs and drug delivery strategies can be developed. This hypothesis will be addressed by the following specific aims: (i) identifying the transport barriers that regulate clot growth and arrest, (ii) mapping the pore structure of clots, and (iii) exploiting interstitial transport to modulate clot growth. The implemented approach relies on applying theories and methods from the field of porous media transport to characterizing transport in tissues. In vitro and in vivo models of vascular injury will be used to measure transport properties in clots and the structure of their interstitial pore space. Constitutive relationships describing solute transport as a function of clot structure and composition will be developed for a range of physiological conditions. Results will be used to assess how known risk factors for thrombosis lead to uncontrolled clot growth and how this process can be physically impeded.Broader Impacts:The proposed studies will develop theoretical and experimental models to predict blood clot growth and test novel therapeutic strategies. This is a potentially transformative outcome since controlling thrombosis is one of the grand challenges in medicine. The research plan integrates with the education plan by creating K-12 outreach programs and undergraduate research opportunities focused on the interface between engineering and biology. Specific educational and outreach objectives include (i) improving middle school students' attitudes towards science with hands-on curriculum, (ii) developing and assessing inquiry-based learning program in bioengineering at a high school with predominantly Latino students, and (iii) establishing a summer undergraduate research program in cellular biomechanics in partnership with the Children's Hospital Colorado for students in the Multicultural Engineering Program at the Colorado School of Mines.