ABR: Melding Mathematical and Theoretical Models of Stress

摘要应激反应是恢复力的主要机制。然而，即使经过近100年的压力研究，我们仍然缺乏一个严格的预测模型，使我们能够知道压力源对个人和群体的影响。缺乏这样一个模型是我们理解应激反应的生态学和病理生理学的长期障碍。本项目将创建并测试第一个应激病理生理定量预测模型。基础将是反应范围模型，一个应力的图形模型。这个图形模型的一个核心组成部分是，长时间激活应激反应会造成磨损。本文将构建一个基于磨损的应力数学模型，并将其与以圈养鸟类为模型的实验室研究相结合。总的来说，该项目将产生一个新的预测定量模型，用于个体以及扩展个体种群如何应对压力源。建立一个综合的概念和定量理论将为解决长期存在的应激生理学问题提供基础，并开辟新的研究领域。该项目将为各级学生提供培训。具体活动将招募妇女和少数民族学生担任研究职位。跨学科训练将教会这些学生如何整合生理和定量技术。研究生每周的研究博客将把研究纳入内分泌学入门课程，从而为课堂提供研究重点。这项工作将通过研究文献的出版物和向公众介绍的方式进行传播。技术摘要定量模型将由一个非线性偏微分方程系统组成，该系统捕获了反应范围概念模型的动态。采用两种已建立的应激和应激反应方案，引入圈养和旋转间歇性应激源应用于圈养鸟类，将根据经验实验对Reactive Scope模型提出的确定性近似的数值解进行测试。关键目标将是了解磨损的时间动态。预测鸟类个体对磨损反应的时间和影响将通过四种方式进行评估：通过测量血浆激素浓度和糖皮质激素受体动态来改变糖皮质激素功能；通过测量心率和心率变异性来衰减交感神经系统反应；通过测量整体活动水平和对新事物的反应来改变行为；通过测量DNA损伤来增加稳态不稳定性，端粒长度和细胞DNA片段的变化证明了这一点。实验室结果将指导对定量模型的反复修改，指出基于更新的定量模型的新实验设计，并为随后的应力和磨损实验室测试形成修订的预测。

Non-technical AbstractThe stress response is a major mechanism of resilience. However, even after nearly 100 years of studying stress we still lack a rigorous predictive model that allows us to know what the impact of stressors on individuals and populations might be. The lack of such a model is a long-standing roadblock to our understanding of the ecology and pathophysiology of stress responses. This project will create and test the first quantitative predictive model of stress pathophysiology. The foundation will be the Reactive Scope Model, a graphical model of stress. A central component of this graphical model is that prolonged activation of a stress response creates wear-and-tear. Here a mathematical model of stress based upon wear-and-tear will be constructed and integrated with laboratory studies using captive birds as models. Overall, the project will generate a new predictive quantitative model for how individuals, and by extension populations of individuals, will respond to stressors. The creation of an integrated conceptual and quantitative theory will provide the foundation to resolve long-standing questions in stress physiology and open up novel areas of research. This project will provide training of students at all levels. Specific activities will recruit women and minority students to research positions. Cross-disciplinary training will teach these students how to integrate physiological and quantitative techniques. A weekly research blog by research students will incorporate the research into an introductory Endocrinology class, thereby providing a research focus to a lecture class. The work will be disseminated through publications in the research literature and presentations to the general public. Technical AbstractThe quantitative model will consist of a system of nonlinear partial differential equations that captures the dynamics of the Reactive Scope conceptual model. Using two established stress and stress response protocols, introduction to captivity and rotating intermittent stressors applied to captive birds, numerical solutions to deterministic approximations suggested by the Reactive Scope model will be tested against empirical experimentation. The key goal will be to understand the temporal dynamics of wear-and-tear. Predicted timing and effects of an individual bird's responses to wear-and-tear will be assessed in four ways: alterations in glucocorticoid function by measuring plasma hormone concentrations and glucocorticoid receptor dynamics; attenuation of sympathetic nervous system responses by measuring heart rate and heart rate variability; changes in behavior by measuring overall activity levels and responses to novel objects; and increases in homeostatic instability by measuring DNA damage as evidenced by changes in telomere length and cellular DNA fragmentation. The laboratory results will guide iterative alterations to the quantitative model, indicate new experimental designs based upon the updated quantitative model, and form revised predictions for subsequent laboratory tests of stress and wear-and-tear.