An Engineering Control System Paradigm for Quantitative Understanding of Hemostasis

用于定量理解止血的工程控制系统范例

• 批准号: 0925202
• 负责人: Babatunde Ogunnaike
• 金额: $ 39.59万
• 依托单位: University of Delaware
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0925202&HistoricalAwards=false
• 关键词: Engineering; Control; System; Paradigm; Quantitative; Engineering; Control; System; Paradigm; Quantitative

0925202OgunnaikeThe primary goal of this research is to develop and validate an engineering control system paradigm for obtaining quantitative insight into how multiple interdependent hemostatic processes interact to control blood loss safely and effectively following vessel injury. A novel quantitative modular modeling and analysis technique for organizing the mechanistic details of this biological process will be developed and validated experimentally. The resulting mathematical model will be used to elucidate mechanisms of hemostatic disorders from a control system perspective, and to generate testable hypotheses about effective treatment. The specific question to be answered is: Quantitatively, how do the various components of the entire hemostatic process work together to produce fast, effective and stable responses to vascular injury under normal conditions? The specific tasks that will be performed are: Task 1: Model Development. Develop a detailed control system block diagram representation of the components of hemostasis, derive mathematical models for each component and integrate into a holistic, comprehensive dynamic model. Task 2: Model Validation (Experimental). In a continuing collaboration the PIs will validate the predictions of each principal module of the overall model against independent experimental data. Task 3: Model Analysis and Hypothesis Generation. Computation studies and theoretical analyses of the model will be carried out; derivation of quantitative insight into pathological disorders from a control system perspective; and generation of hypothesis regarding effective treatment regimens in terms of optimal compensation for component malfunction responsible for the identified disorder. Intellectual Merit Systemic changes in life sciences research have created opportunities for mathematical modeling to play a major role in developing quantitative and predictive understanding of complex biological phenomena. With ever improving experimental capabilities facilitating the acquisition of more refined data on the most intricate cellular and molecular mechanisms, increasing computational power has steadily steered mathematical modeling in systems biology towards adopting ?bigger and more complex? representations of these complex systems. For the specific problem of hemostasis there are currently no holistic quantitative models of the complete hemostasis process perhaps because many of the constituent components are quite complex in their own right, and a ?standard? attempt at developing a holistic model is not likely to be very useful. By recognizing that at the heart of hemostasis is an automatic biological control system, this research aims to deploy concepts from engineering control systems to develop a comprehensive hemostatic process model that achieves fidelity without sacrificing analytical tractability. The PIs envision two kinds of primary impact for this research: (i) Technical: an improved quantitative understanding of how this biological process is regulated under normal circumstances, and how the characteristics of the whole emerge from the connection of the individual component parts, with implications for clinical practice in the form of more precise treatment of hemophilia and thrombophilia; (ii) Methodological: demonstrating how to achieve high-fidelity and analytical tractability simultaneously in models of extremely complex biological phenomena. Broader Impact At the heart of the evolving undergraduate training program is the issue of how to integrate biology within the classical chemical engineering curriculum. This research addresses theoretically and with experimental validation, issues that are perfect for introducing students to biological control systems, and how to employ such simulation tools as SIMULINK for modeling and understanding such systems. The results of this research will be integrated into the teaching curricula and widely disseminated through publications and presentations to other educators and researchers. In addition, the PI, as a minority himself, is committed to recruiting under-represented groups into the chemical engineering discipline in general and systems biology research in particular, and should be able to attract minority students to participate in this effort.

这项研究的主要目标是0925202，这是为了获得工程控制系统范式的开发和验证，以获取定量洞察力，以了解多个相互依存的止血过程如何在血管损伤后安全有效地控制失血。将通过实验开发和验证一种新型的定量模块化建模和分析技术，用于组织此生物学过程的机械细节。最终的数学模型将用于从控制系统的角度阐明止血疾病的机制，并产生有关有效治疗的可检验假设。要回答的具体问题是：定量，整个止血过程的各个组成部分如何共同起作用，以在正常情况下对血管损伤产生快速，有效和稳定的反应？将要执行的特定任务是：任务1：模型开发。开发止血成分的详细控制系统框图图表示，为每个组件提供数学模型，并集成到整体，全面的动态模型中。任务2：模型验证（实验）。在持续的协作中，PI将根据独立的实验数据来验证总体模型的每个主要模块的预测。任务3：模型分析和假设产生。该模型的计算研究和理论分析将进行；从控制系统的角度推导了对病理疾病的定量洞察力；以及关于有效治疗方案的假设，该假设是针对鉴定疾病的最佳补偿分量故障的最佳补偿。生活科学研究的智力优点变化为数学建模创造了机会，以在对复杂生物学现象的定量和预测理解中发挥重要作用。通过提高实验能力，可以促进对最复杂的细胞和分子机制的获取更精致的数据，因此，增加的计算能力在系统生物学中稳步转向数学建模，以采用更大，更复杂的？这些复杂系统的表示。对于止血的具体问题，目前没有完整止血过程的整体定量模型，也许是因为许多组成部分本身都非常复杂，并且是“标准”？尝试开发整体模型不太可能非常有用。通过认识到止血的核心是一种自动生物控制系统，该研究的目的是部署工程控制系统的概念，以开发一种综合的止血过程模型，该模型在不牺牲分析障碍的情况下实现忠诚度。 PIS设想了这项研究的两种主要影响：（i）技术：对这种生物过程在正常情况下如何调节该生物过程的定量理解得到了改进，以及整个组件部分之间的特征如何从单个组件部分的联系中出现，对临床实践的含义更为精确地治疗血液友善和血栓友善； （ii）方法论：演示如何在极其复杂的生物学现象模型中同时实现高保真性和分析性障碍。在不断发展的本科培训计划的核心方面，更广泛的影响是如何将生物学整合到古典化学工程课程中。这项研究在理论上和实验验证方面解决了问题，这些问题非常适合将学生介绍给生物控制系统，以及如何使用Simulink等模拟工具来建模和理解此类系统。这项研究的结果将融入教学课程中，并通过出版物和演讲向其他教育者和研究人员进行广泛传播。此外，作为少数群体本人，PI致力于将代表性不足的群体招募到整个化学工程学科，尤其是系统生物学研究，应该能够吸引少数派学生参加这项工作。