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

职业：关于血凝块生长生物力学的综合研究和教育计划

• 批准号: 1351672
• 负责人: Keith Neeves
• 金额: $ 43.56万
• 依托单位: Colorado School of Mines
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1351672&HistoricalAwards=false
• 关键词: CAREER; integrated; research; education; program

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.

1351672 neeves血凝块构成了一个精巧的工程系统，在这个系统中，一种复杂的液体在受伤部位变成了一个固体塞。稳定止血凝块的设计目的是在不阻塞血管的情况下止血，承受血液流动的力量，并随着伤口愈合过程缓慢溶解。这些事件中的任何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，但止血凝块和血栓性凝块之间的机制差异在很大程度上仍然未知。PI实验室和其他实验室最近的发现表明，阻碍溶质从凝块核心处的运输可能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质间隙内的运输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，那么将这种生物物理机制与传统的生化机制结合起来，可能会更有效地治疗血栓形成。智力优势：本提案通过发展血块组成和生长之间的定量关系来研究一个重要的生理系统。传统的凝块形成模型主要关注凝血反应和血小板信号传导的动力学过程。提出的研究建立在以前的模型上，将溶质间质运输作为凝块生长的关键机制。有了更有能力的预测方法，就可以开发出更好的药物和给药策略。这一假设将通过以下具体目标来解决：(i)确定调节血块生长和停止的运输障碍，（ii）绘制血块的孔隙结构，以及（iii）利用间质运输来调节血块生长。所实现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。体外和体内血管损伤模型将用于测量血块的运输特性及其间质孔空间的结构。描述溶质运输作为凝块结构和组成的功能的本构关系将在一系列生理条件下发展。结果将用于评估血栓形成的已知危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：拟议的研究将建立理论和实验模型来预测血凝块的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的重大挑战之一。该研究计划与教育计划相结合，通过创建K-12扩展计划和本科生研究机会，重点关注工程和生物学之间的界面。具体的教育和推广目标包括(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基于探究的生物工程学习计划。（iii）与科罗拉多儿童医院合作，为科罗拉多矿业学院多元文化工程专业的学生建立一个细胞生物力学暑期本科生研究项目。