Role of the circadian rhythm on endocannabinoid response to an acute stress

项目摘要 心血管（CV）疾病是美国的主要死亡原因。夜班和轮班工作， 劳动力，与心理社会压力和CV疾病的发生率较高相关，表明 当身体处于睡眠和恢复的最佳状态时，清醒和活动对一个人的健康有害。急性 压力源，表现为对心理社会压力和适度锻炼的反应而产生的高度情绪 可触发CV事件，然而，潜在的生理学仍不清楚。内源性大麻素（eCB）是脂质 信使，调节情绪和生理反应的压力，也已被证明 调节CV功能。我和同事最近证明了一个强大的内源性昼夜节律， 循环eCB的基础水平，在生物学夜间出现波谷。然而，eCB的昼夜变化 反应性，即对急性应激的反应从基线的变化，仍然不清楚。eCB反应的差异 以及昼夜节律系统中对急性应激的相关CV反应性提供了一种合理的途径， 可能是轮班工人发生CV疾病的风险基础。因此，我的目标是测试假设， 循环eCB响应于（a）急性心理社会应激和（B）轻度躯体应激的变化 （运动）取决于昼夜节律阶段，并将与情绪和CV反应性的变化相关。 拟议的研究将利用心理社会压力（抑郁）对情绪的相反影响。 情绪）和运动压力（改善情绪），以进一步研究eCB如何调节情绪处理， 与CV功能有关。此外，由于美国黑人的年龄调整CV疾病死亡率最高， 坚持表现出不同的反应，以强调这一建议将测试假设，黑人 与白人相比，白人对心理社会和躯体压力源的eCB反应减弱。这些目标将 通过调整睡眠-觉醒周期的多日昼夜节律方案（无时间提示的昏暗照明）实现 到重复18小时周期，使得在许多周期之后，所有行为在所有昼夜节律相位上均匀地发生。 评估包括来自唾液褪黑激素的昼夜节律相位和幅度、来自血液的循环eCB 血浆和情绪CV功能的相关标志物将包括自主神经功能和 止血标志物。该方案将在40名健康成年人中进行，作为我的一个额外组成部分。 主要导师的活动项目（R 01 HL 142064，PI，Steven Shea）。阐明影响压力的机制 昼夜节律系统的反应性整合了我之前的训练，是我研究中的一个逻辑进展 这将为评估循证干预措施的效用提供有价值的信息。实现 我的长期目标是成为一名独立的科学家，将压力和昼夜节律研究转化为 实验室和社区，这K 01将提供进一步的培训，在以下领域：1）标准化和 压力协议的评估; 2）检查压力时间顺序的高级统计培训 标志物;和3）关于突发CV事件的病因学和预防以及CV健康评估的知识。

Project Summary Cardiovascular (CV) disease is the leading cause of death in the US. Night and rotating shift work, ~20% of the labor force, is associated with a greater incidence of both psychosocial stress and CV disease suggesting that wakefulness and activity when the body is optimized for sleep and recovery is harmful to one’s health. Acute stressors in the form of both heightened emotions in response to a psychosocial stress and moderate exercise can trigger a CV event, however, the underlying physiology remains unclear. Endocannabinoids (eCB) are lipid messengers that modulate the emotional and physiological response to stress and have also been demonstrated to regulate CV function. Colleagues and I have recently demonstrated a robust endogenous circadian rhythm in basal levels of circulating eCBs with a trough during the biological night. However, the circadian variation in eCB reactivity, change from baseline in response to an acute stress, remains unclear. A difference in eCB response and associated CV reactivity to an acute stress across the circadian system provides a plausible pathway that could underlie risks for development of CV disease in shift workers. Thus, I aim to test the hypotheses that changes of circulating eCBs in response to (a) an acute psychosocial stress and (b) a mild somatic stress (exercise) are dependent upon circadian phase and will correlate with changes in emotional and CV reactivity. The proposed research will take advantage of the opposite effects on mood of psychosocial stress (depressed mood) and exercise stress (improved mood) to further examine how eCB regulation of emotional processing is related to CV function. Additionally, as Black Americans have the highest age-adjusted CV disease mortality and persistently demonstrate differential responses to stress this proposal will test the hypothesis that Blacks compared to Whites will have attenuated eCB responses to psychosocial and somatic stressors. These aims will be achieved via a multi-day circadian protocol (dim lighting free of time cues) with sleep-wake cycles adjusted to recurring 18h cycles so that after numerous cycles all behaviors occur evenly across all circadian phases. Assessments include circadian phase and amplitude from salivary melatonin, circulating eCBs from blood plasma and mood from questionnaires. Relevant markers of CV function will include autonomic function and markers of hemostasis. This protocol will be performed in 40 healthy adults as an additional component to my primary mentor’s active project (R01HL142064, PI, Steven Shea). Elucidation of mechanisms that impact stress reactivity across the circadian system integrates my prior training and is a logical progression in my research career that will provide valuable information for evaluating the utility of evidence-based interventions. To achieve my long-term goal of becoming an independent scientist translating stress and circadian research between the laboratory and community, this K01 will provide further training in the following areas: 1) Standardization and assessment of stress protocols; 2) Advanced statistical training for examining the temporal order of stress markers; and 3) Knowledge on the etiology and prevention of sudden CV events and assessment of CV health.