Synergistic Effects of Stress and Traffic-Related Air Pollution on Cardiovascular Health

摘要 心血管疾病(CVD)是美国主要的死亡原因，对 较低的社会经济地位(SEP)-这种差异被归因于对两种交通工具的暴露程度增加- 相关的空气污染(陷阱)和慢性社会压力。许多流行病学和毒理学研究表明 暴露在慢性压力下会极大地增加陷阱的易感性，尽管现在有越来越多的证据表明 提示TRAP也可能强烈影响下丘脑-垂体-肾上腺(HPA)轴功能和急性 压力反应，使相互作用的方向性和解释复杂化。重要的是要理清这些 两个模型，以开发更具生物学基础的流行病学模型结构，并完善设计 压力和污染的时空暴露指标。最终，这项工作将有助于更好地识别 对易感人群进行评估，并确定有效的干预措施，以改善健康状况，缩小健康差距。 然而，这样做是具有挑战性的，因为压力和陷阱都是复杂的暴露，具有不同的多系统 影响。研究表明，压力会强烈影响免疫、内分泌和新陈代谢功能，但影响很大。 对时间敏感，因为急性和慢性压力表现得非常不同。陷阱是一种高度复杂的化学混合物， 每一种都有非常不同的生理影响。在这份Victer提案中，我们建立了一个跨学科团队来 量化和比较慢性和急性应激、陷阱以及它们在塑造心血管方面的多重交互作用 功能。我们独一无二地准备绘制这片未被探索的地形，就像在 大气科学与机械工程(韦克斯勒)、心血管调节和自主神经功能 接触科学和社会环境流行病学(Clougherty)。为此，我们将使用 独特的捕集器输送系统，具有实时浓度和化学成分测量，经过良好验证 大鼠慢性和急性应激反应模型、心血管时间分辨测量 功能(遥测)，以及多个时间点的慢性和急性应激标志物的生物概况(例如， 皮质醇、C反应蛋白、细胞因子)，以量化和比较上述两个概念模型中的方向性。 我们假设：(1)诱捕器成分(轻型和重型车辆)对心血管的影响不同 (2)在研究过程中，慢性应激可增强动物对TRAP的心血管反应； (3)TRAP可能会降低动物对应激挑战的心血管韧性。这项研究将建立一个 具有互补专业知识的跨学科团队，以研究压力之间相互作用的复杂性 和污染暴露--一个与服务不足和边缘化人群的健康差距密切相关的问题 社区，特别是心血管疾病，这是导致死亡的主要原因。该团队将共同努力，整合结果 三个目标中的一个目标转化为后续R01应用的假设。

ABSTRACT Cardiovascular disease (CVD), the leading cause of death in the U.S., disproportionately impacts persons of lower socioeconomic position (SEP) -- a disparity that has been attributed to heightened exposures to both traffic- related air pollution (TRAP) and chronic social stressors. Many epidemiologic and toxicologic studies have shown that exposures to chronic stress can vastly increase susceptibility to TRAP, though growing evidence now suggests that TRAP may also strongly impact hypothalamic-pituitary-adrenal (HPA)-axis function and acute stress response, complicating the directionality and interpretation of interactions. It is critical to disentangle these two models, to develop more biologically-grounded epidemiologic model structures, and refine the design of space-time exposure metrics for both stress and pollution. Ultimately, this work will help to better identify susceptible populations, and identify effective interventions to improve health and reduce health disparities. Doing so is challenging, however, as both stress and TRAP are complex exposures with diverse multi-systemic impacts. Stress is shown to strongly impact immune, endocrine, and metabolic function, but effects are highly time-sensitive, as acute and chronic stress manifest very differently. TRAP is a highly complex mix of chemicals, each with very different physiologic impacts. In this ViCTER proposal, we establish an interdisciplinary team to quantify and compare chronic and acute stress, TRAP, and their multiple interactions, in shaping cardiovascular function. We are uniquely poised to map this unexplored terrain, as accomplished senior investigators in atmospheric science and mechanical engineering (Wexler), cardiovascular regulation and autonomic function (Chen), and exposure science and social-environmental epidemiology (Clougherty). To do so, we will use a unique TRAP delivery system with real-time concentration and chemical composition measures, a well-validated model for generating chronic and acute stress responses in rats, time-resolved measures of cardiovascular function (telemetry), and biological profiling at multiple time points for chronic and acute stress markers (e.g., cortisol, CRP, cytokines), to quantify and compare directionality in the two conceptual models described above. We hypothesize that: (1) TRAP composition (light- vs. heavy-duty vehicles) differently impact cardiovascular function; (2) Chronic stress may heighten animals’ cardiovascular response to TRAP, over the course of study; (3) TRAP may compromise animals’ cardiovascular resilience to stress challenge. This study will establish an interdisciplinary team with complementary expertise to examine complexities in the interactions among stress and pollution exposures – an issue profoundly relevant to health disparities in under-served and marginalized communities, especially for CVD, the leading cause of death. The team will work together to integrate the results of the three aims into hypotheses for subsequent R01 applications.