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

职业：蛋白质稳态到异稳态：细胞和有机体水平应激反应的整合

• 批准号: 1553657
• 负责人: Haruka Wada
• 金额: $ 101.81万
• 依托单位: Auburn University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1553657&HistoricalAwards=false
• 关键词: CAREER; Proteostasis; Allostasis; Integration; Cellular

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.

压力事件可以永久改变有机体的功能。 成年人的这些相同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至关重要。然而，这一直具有挑战性，部分原因是尽管已经在细胞和整个有机体水平上研究了对压力的反应，但科学家们尚未成功地将整个动物的压力与细胞后果联系起来。该项目的目标是 1) 提高我们对两个层面的压力反应的理解，2) 批判性地评估压力反应的调节方式。该项目还旨在提高阿拉巴马州农村地区的科学素养和基于探究的科学教育。首先，该项目将有助于更全面地了解生物体如何应对压力，并将教导中学生和高中生如何在分子和整个动物水平上相互关联。其次，描述应激反应调节的模型已应用于评估疾病风险因素，例如肥胖和社会经济状况。该项目将教育阿拉巴马公立学校的学生了解肥胖、生活方式和饮食的后果以及如何克服压力。最后，阿拉巴马州东南部科学博览会项目的参与度和质量极低，尽管此类项目为实施基于探究的科学教育方法提供了绝佳的机会。该项目将与生物教师合作，提供培训、指导和举办科学博览会项目的机会，以激发人们对生物学的兴趣，激发科学职业生涯，并提高历史上 STEM 教育服务不足的地区的科学素养。概念化和研究压力一直具有挑战性，因为压力反应跨越多个生物尺度，而且压力的后果往往是非线性的。这种整合的缺乏是该领域的主要障碍，并且以糖皮质激素和热休克蛋白为重点的应激反应研究很好地证明了这一点。因此，该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，该项目将通过确定 1) 糖皮质激素是否升高 HSP 和相关转录因子，以及 2) 受热休克反应途径调节的蛋白质稳态破坏是否引发糖皮质激素反应，来测试 HSP 和糖皮质激素相互启动反应，为后续应激源做好准备的假设。热休克蛋白和糖皮质激素的升高既有保护作用，也有破坏作用。动态平衡模型概念化了压力的非线性性质，但该模型尚未经过明确测试。该项目还将利用斑胸草雀通过预先的热调节来调整其耐热性，通过测试这样的假设来评估动态平衡模型：经过预调节的鸟类比没有接触过压力源的鸟类会引起更大的热休克和糖皮质激素反应，从而保护个体免受与压力相关的生殖和免疫功能抑制。通过定义 HSP 和糖皮质激素反应之间的直接和相互关系，该项目将描述 HSP 反应的有机协调特征，并为糖皮质激素从保护作用转变为破坏作用提供分子基础。此外，该项目将对动态平衡模型以及该模型是否适用于营养应激以外的应激源进行深入评估。