Stress Biomarkers: Biological Meaning of Field-Friendly Salivary Measures

描述（由申请人提供）：压力和情绪影响健康。为了减少其代价高昂的健康后果，必须了解它们改变生物过程的机制。下丘脑-垂体-肾上腺（HPA）轴在将心理社会经验转换为与健康相关的身体变化方面起着关键作用，HPA压力研究正在蓬勃发展。唾液皮质醇的测量提供了一个压力的HPA活动的“生物标志物”，用于流行病学研究，揭示皮质醇与工作压力，创伤，抑郁，疲劳，少数民族地位，心血管疾病和癌症死亡率。实验室工作已经将HPA活性分解为生物学上重要的调节组分（例如，负反馈、中枢驱动、应激反应），并提供了这些成分的实验室探测器，但几乎没有努力将实地研究和实验室研究联系起来。现场友好的压力生物标志物的心理社会相关性正在确定，但我们对它们的生物学意义知之甚少。标记物的选择是基于易用性，而不是基于与已知健康相关的特定生物过程的经验联系。该项目将把现场和实验室工作联系起来，提高两者的价值，以及每年花费在唾液皮质醇测定上的数百万美元的价值。皮质醇觉醒反应（CAR）、觉醒水平和昼夜下降是常用的野外应激生物标志物。每一个可能提供不同的信息HPA轴调节，但这还没有得到明确的审查。CAR是使用最广泛的。其实验室相关性已被研究，但很少被承认-它似乎更密切地联系到肾上腺敏感性比理论上更有趣的中央HPA措施。赋予野外生物标志物以生物学意义将促进更精确的假设，以及更有效的生物采样来测试它们。实验室探针将赋予唾液测量的生物学意义，它们本身受到相互作用的遗传和发育因素的影响。例如，童年的逆境会显著降低HPA反馈的敏感性，但这种影响只在具有HPA基因（CRHR 1）特定变体的受试者中观察到，如果忽略遗传效应，这种影响可能仍然无法检测到。如果基因影响实验室探针，并且场标记与这些探针连接，则基因将影响场标记。忽视这种影响将破坏将心理社会变量与压力生物标志物联系起来的努力。这种现象的记录和相关基因的初步探索对于防止昂贵的流行病学研究中的假阴性结果和复制失败至关重要，我们希望将使用我们在该项目中确定的更有效和更有生物学意义的生物标志物。在这项研究中，我们将使用实验室探针为现场友好的HPA生物标志物赋予生物学意义，确定最有效和最有意义的探针组，并提供有关遗传因素的初步数据，这些遗传因素可能会破坏使用压力生物标志物进行流行病学压力研究的假设检验。这项工作将加深对HPA轴的理解，并提高未来用于现场应力研究的每一美元的价值。

DESCRIPTION (provided by applicant): Stress and emotion impact health. To reduce their costly health consequences, mechanisms through which they alter biological processes must be understood. The hypothalamic-pituitary adrenal (HPA) axis plays a key role in transducing psychosocial experience into bodily changes relevant to health, and HPA stress research is exploding. Salivary cortisol measures provide a stress "biomarker" of HPA activity for use in epidemiological studies, revealing that cortisol is associated with job stress, trauma, depression, fatigue, minority status, cardiovascular disease, and cancer mortality. Laboratory work has dissected HPA activity into biologically important regulatory components (e.g., negative feedback, central drive, stress reactivity) and provides laboratory probes of these components, but there has been little effort to link field and laboratory studies. Psychosocial correlates of field-friendly stress biomarkers are being identified, but we know little about their biological meaning. Markers have been chosen based on ease of use, not on empirical links to specific biological processes of known health relevance. This project will link field and laboratory work, enhancing the value of both, and the value derived from the millions of dollars spent yearly on salivary cortisol assay. The cortisol awakening response (CAR), awakening level, and diurnal decline are commonly used field stress biomarkers. Each likely provides different information about HPA axis regulation, but this has not been explicitly examined. CAR is the most extensively used. Its laboratory correlates have been studied, but are rarely acknowledged - it appears more closely linked to adrenal sensitivity than to theoretically more interesting central HPA measures. Giving biological meaning to field-friendly biomarkers will foster more precise hypotheses, and more efficient bio-sampling to test them. The laboratory probes which will attach biological meaning to salivary measures are themselves influenced by interacting genetic and developmental factors. Childhood adversity, for example, significantly reduces HPA feedback sensitivity, but this effect is only seen in subjects with a particular variant of an HPA gene (CRHR1) and can remain undetected if the genetic effect is ignored. If genes impact laboratory probes, and the field markers link to these probes, genes will impact the field markers. Ignoring this impact will undermine efforts to link psychosocial variables to the stress biomarkers. Documentation of this phenomena and preliminary exploration of relevant genes will be critical to prevent false negative results and replication failures in expensive epidemiological studies that we hope will use the more efficient and biologically meaningful biomarkers we identify in this project. In this study, we will use laboratory probes to give biological meaning to field-friendly HPA biomarkers, identify the most efficient and meaningful set of probes to use, and provide preliminary data on genetic factors that can undermine hypothesis testing in epidemiological stress research using stress biomarkers. This work will deepen understanding of the HPA axis and enhance the value of every future dollar spent on field stress studies.