Understanding the limits of human heat tolerance from the cell to the whole-body response

温度调节是人类生存的重要方面。然而，运动和/或暴露于高温环境可能导致体温危险升高。为了抵消这种增加，高度发达的自主热效应反应（皮肤血管舒张和出汗）被激活，以促进热应激期间的全身热损失。使用世界上唯一的空气量热仪（一种提供人体散热的非常精确测量的设备），我们表明，热效应器响应的生理控制以及因此全身热损失可以作为几个个体间因素的函数而变化（例如，年龄、性别、其他）和个体内因素（例如，健身、水合作用、暴露持续时间）。这包括与感觉受体的激活相关的非热因素的影响（例如，压力感受器、代谢感受器）。虽然我们基于热量的研究促进了我们对限制人类耐热性因素的理解，但我们评估细胞热应激反应的新兴工作正在揭示导致热相关脆弱性的复杂细胞机制。为了继续推进这一重要工作，我正在寻求更换旧的、不适当的仪器，并获得新的工具，以提高我们进行这一创新研究的能力，并最大限度地提高我们的研究成果。具体而言，该提案的目的是通过更换我们的热量计过时的数据采集接口平台来扩大我们研究活动的范围和影响，以监测生理反应（即，可扩展的系统，其能够添加能够容纳在一个系统下记录多个生理变量所需的一系列硬件接口的数据采集系统）。这将消除我们对采用不同数据采集系统和软件平台的多个监测站的依赖，并为我们基于热量测定的研究中其他生理变量的监测提供未来扩展的能力。此外，我们正在寻求更换旧工具并获得新工具（例如，离心机、平台摇杆、摆动旋转器、蛋白质印迹成像系统、蛋白质印迹电泳系统），以满足我们的需求，并提高我们评估蛋白质和基因反应的能力，以研究热脆弱性背后的细胞机制。这将使我们能够弥合从细胞到全身反应介导人类耐热性的因素的理解上的差距，帮助我们实现下一个发现和创新的梯队。重要的是，它将吸引新的受训人员队伍，并推动新一代科学发展文化，以应对工业和受地球变暖引发的极端高温影响的其他人口部门所面临的现实挑战。

Temperature regulation is a vital aspect of human survival. However, exercise and/or exposure to hot environments can lead to dangerous increases in body temperature. To offset this increase, highly developed autonomic thermoeffector responses (cutaneous vasodilation and sweating) are activated to facilitate whole-body heat loss during heat stress. Using the world's only air calorimetry (a device that provides a very precise measurement of the heat dissipated by the human body), we showed that physiological control of thermoeffector responses and therefore whole-body heat loss can vary as a function of several inter-individual factors (e.g., age, sex, other) and intra--individual factors (e.g., fitness, hydration, exposure duration). This includes the influence of non-thermal factors associated with the activation of sensory receptors (e.g., baroreceptors, metaboreceptors). While our calorimetry-based research has advanced our understanding of the factors limiting human heat tolerance, our emerging work evaluating the cellular heat stress response is uncovering the complex cellular mechanisms that contribute to heat-related vulnerabilities. To continue advancing this important work, I am seeking to replace older, inadequate instruments and obtain new tools to increase our capacity to conduct this innovative research and maximize our research output. Specifically, the aim of this proposal is to expand the scope and impact of our research activities by replacing our calorimeter's antiquated data acquisition interface platform for the monitoring of physiological responses (i.e., scalable system enabling the addition of a data acquisition system capable of accommodating a range of hardware interfaces needed to record multiple physiological variables under one system). This would eliminate our dependence on multiple monitoring stations employing different data acquisition systems and software platforms and provide capacity for future expansion for the monitoring of other physiological variables in our calorimetry-based studies. Further, we are seeking to replace older tools and acquire newer instruments (e.g., centrifuge, platform rocker, waving rotator, Western blot imaging system, Western blot electrophoresis system) to meet our needs and enhance our capacity to evaluate protein and gene responses to study the cellular mechanisms underlying heat vulnerabilities. This would allow us to bridge the gap in our understanding of the factors mediating human heat tolerance from the cell to the whole-body response, helping us achieve the next echelon of discovery and innovation. Importantly, it will attract a new cadre of trainees and drive a new generation and culture of scientific growth to address real-world challenges faced by industry and other sectors of our population affected by extreme heat spurred by a warming planet.