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

血液凝块构成了一个精心设计的系统，在这个系统中，复杂的液体在损伤部位转化为固体塞子。稳定的止血凝块可以在不阻塞血管的情况下止血，抵抗血液流动的力量，并在伤口愈合过程中慢慢溶解。这些事件中的任何一种不稳定都可能导致过度凝血或血栓形成，这是导致死亡的主要原因。尽管在血栓形成的生物化学和细胞生物学方面有广泛的知识基础，但止血血栓和血栓形成之间的机制差异仍然很大程度上是未知的。来自PI实验室和其他实验室的最新发现表明，阻止溶质从血栓核心向外运输是预防血栓形成的一种机制。基于这一证据，提出的研究假设是凝血因子和血小板激动剂在血细胞间隙内的运输是血栓生长的关键调节因素。如果这一假设被证明是正确的，那么将这种生物物理机制与传统的生化机制结合起来可能会导致更有效的血栓治疗。智力上的优点：这一建议通过建立凝块成分和生长之间的定量关系来研究一个重要的生理系统。传统的血栓形成模型主要关注凝血反应和血小板信号转导的动力学过程。拟议的研究建立在先前模型的基础上，将组织间隙溶质运输作为凝块生长的关键机制。有了更强大的预测方法，就可以开发出更好的药物和药物输送策略。这一假说将通过以下具体目标来解决：(I)识别调节凝块生长和停滞的运输障碍，(Ii)绘制凝块的孔结构图，以及(Iii)利用间质运输来调节凝块生长。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被用来测量凝块的运输特性及其间质孔隙的结构。描述作为凝块结构和组成的函数的溶质传输的本构关系将在一系列生理条件下建立。研究结果将用于评估已知的血栓形成风险因素如何导致血栓不受控制的增长，以及这一过程如何受到物理上的阻碍。广泛影响：拟议的研究将开发理论和实验模型，以预测血栓增长并测试新的治疗策略。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。该研究计划与教育计划相结合，创建了K-12扩展计划和专注于工程学和生物学之间的接口的本科生研究机会。具体的教育和外展目标包括：(I)通过实践课程改善中学生对科学的态度；(Ii)在一所以拉丁裔学生为主的高中开发和评估生物工程探究式学习计划；以及(Iii)与科罗拉多州儿童医院合作，为科罗拉多矿业学院多元文化工程计划的学生设立细胞生物力学暑期本科研究计划。

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.