CAREER: Proteostasis to Allostasis: Integration of Cellular- and Organismal-level Stress Responses

压力事件可以永久地改变生物体的功能。成年人同样的情况也可以追溯到生命早期的事件。因此，了解生物体如何应对环境压力是至关重要的。然而，这是具有挑战性的，部分原因是尽管对压力的反应已经在细胞和整个生物体水平上进行了研究，科学家们还没有成功地将压力与整个动物和细胞后果联系起来。该项目的目标是：1)提高我们对两个层次的压力反应的理解；2)批判性地评估压力反应是如何调节的。该项目还旨在提高阿拉巴马州农村地区的科学素养和以探究为基础的科学教育。首先，这个项目将有助于更全面地了解生物体如何应对压力，并将教中学生和高中生分子和整个动物水平上的事件是如何相互联系的。其次，描述应激反应调节的模型已被用于评估疾病的危险因素，如肥胖和社会经济地位。这个项目将教育阿拉巴马公立学校的学生关于肥胖、生活方式和饮食的后果以及如何克服压力。最后，阿拉巴马州东南部的科学博览会项目的参与度和质量都非常低，尽管这些项目为实施基于探究的科学教育方法提供了很好的机会。该项目将与生物教师合作，提供培训、指导和开展科学展览项目的机会，以激发人们对生物学的兴趣，激发科学事业，并提高STEM教育历史上缺乏的地区的科学素养。压力的概念化和研究一直具有挑战性，因为压力反应跨越多个生物尺度，而压力的后果往往是非线性的。缺乏整合是这一领域的主要障碍，以糖皮质激素和热休克蛋白为重点的应激反应研究就是很好的例子。因此，本项目将描述涉及热休克蛋白和糖皮质激素的综合应激反应。具体来说，本项目将通过确定是否1)糖皮质激素升高热休克蛋白和相关转录因子，以及2)由热休克反应途径调节的蛋白质平衡的中断，引发糖皮质激素反应，来验证热休克蛋白和糖皮质激素在准备后续应激源时相互启动反应的假设。热休克蛋白和糖皮质激素的升高具有保护和破坏作用。异稳态模型概念化了应力的非线性性质，但该模型尚未得到明确的测试。该项目还将利用斑马雀通过事先的热调节来调节其耐热性，通过测试预先条件反射的鸟类比没有事先暴露于压力源的鸟类产生更大的热休克蛋白和糖皮质激素反应，从而保护个体免受与压力相关的生殖和免疫功能抑制的假设，来评估适应稳态模型。通过定义热休克蛋白和糖皮质激素反应之间的直接和相互关系，该项目将描述热休克蛋白反应的有机协调，并为糖皮质激素从保护作用到破坏作用的转换提供分子基础。此外，该项目将提供一个深入的评估适应模型，以及该模型是否适用于营养应激以外的应激源。

Stressful events can permanently modify how an organism functions. Those same conditions in adults can also be traced back to events early in life. Therefore understanding how organisms respond to environmental stress is crucial. However, this has been challenging partly because although responses to stress have been studied at but the cellular and whole organism level, scientists have not yet made a successful link between stress to the whole animal and the cellular consequences. The goals of the project are to 1) improve our understanding of stress responses at both levels and 2) critically evaluate how the stress response is regulated. This project also aims to improve science literacy and inquiry-based science education in rural regions of Alabama. First, this project will contribute to a more holistic view of how organisms respond to stress, and will teach middle and high-school students how events at molecular and whole-animal levels are interconnected. Second, models describing stress response regulation have been applied to evaluate diseases risk factors, e.g., obesity and socioeconomic status. This project will educate Alabamian public school students about the consequences of obesity, lifestyle, and diet and how to overcome stress. Finally, the participation in, and quality of, science fair projects in southeastern Alabama has been extremely low, although such projects provide a great opportunity to implement an inquiry-based approach to science education. In collaboration with biology teachers, the project will provide training, mentorship, and opportunities to conduct science fair projects to spark interests in biology, inspire scientific careers, and increase science literacy in regions historically underserved in STEM education.Conceptualizing and studying stress has been challenging because stress responses extend across multiple biological scales, and the consequences of stress are often non-linear. This lack of integration is a major obstacle in this field, and is well exemplified by glucocorticoid- and heat shock protein-focused studies of stress responses. Therefore, this project will characterize an integrative stress response involving both HSPs and glucocorticoids. Specifically, this project will test the hypothesis that HSPs and glucocorticoids prime each other's response in preparation for subsequent stressors by determining whether 1) glucocorticoids elevate HSP and associated transcription factor and 2) a disruption in proteostasis, as regulated by the heat shock response pathway, elicits glucocorticoid responses. Elevation of HSPs and glucocorticoids has both protective and damaging effects. The allostasis model conceptualizes this non-linear nature of stress, yet this model has not been explicitly tested. Using zebra finches which adjust their heat tolerance with prior heat-conditioning, the project will also evaluate the allostasis model by testing the hypothesis that pre-conditioned birds elicit greater HSP and glucocorticoid responses than birds with no prior exposure to the stressor, thereby protecting individuals from stress-related suppression of reproductive and immune functions. By defining the direct and reciprocal relationship between HSP and glucocorticoid responses, this project will characterize organismal orchestration of the HSP response and provide a molecular basis for the switch from protective to damaging effects of glucocorticoids. Furthermore, this project will provide an in-depth evaluation of the allostasis model and whether this model applies to a stressor beyond nutritional stress.