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

项目摘要 心血管疾病是美国人的主要死亡原因。夜班和轮班工作，大约20%的 劳动力，与心理社会压力和心血管疾病的发病率都更高相关，这表明 身体处于最佳睡眠和恢复状态时的清醒和活动对人的健康有害。急性 应激源既包括对心理社会压力的高度反应的情绪，也包括适度的锻炼 可以触发心血管事件，然而，潜在的生理学仍不清楚。内源性大麻素(ECB)是脂类 调节情绪和生理对压力的反应的信使也已经被证明 调节心血管功能。我和我的同事最近展示了一种强大的内源性昼夜节律 在生物之夜，循环ECB的基础水平与低谷。然而，欧洲央行的昼夜变化 反应性是对急性应激反应的基线变化，目前尚不清楚。欧洲央行的反应不同 在昼夜节律系统中，与急性应激相关的CV反应提供了一条看似合理的途径 可能是轮班工人发生心血管疾病的潜在风险。因此，我的目标是检验以下假设 循环ECB对(A)急性心理社会应激和(B)轻度躯体应激反应的变化 (锻炼)取决于昼夜节律阶段，并将与情绪和CV反应性的变化相关。 建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(改善的情绪)，以进一步研究欧洲央行对情绪处理的调控是如何 与CV功能相关。此外，由于美国黑人的年龄调整后心血管疾病死亡率和 坚持不懈地表现出不同的反应来强调这一提议将检验黑人的假设 与白人相比，白人将减弱欧洲央行对心理社会和躯体应激源的反应。这些目标将 通过调整睡眠-唤醒周期的多天昼夜节律(没有时间提示的昏暗灯光)来实现 到重复的18小时周期，这样在无数个周期之后，所有的行为都会均匀地出现在所有的昼夜节律阶段。 评估包括唾液褪黑激素的昼夜节律和幅度，血液循环中的ECB 调查问卷中的血浆和情绪。心血管功能的相关标志物包括自主神经功能和 止血的标志物。该方案将在40名健康成年人身上执行，作为我的 初级导师的积极项目(R01HL142064，Pi，Steven Shea)。阐明影响应力的机制 整个昼夜节律系统的反应结合了我之前的训练，在我的研究中是一个合乎逻辑的进展 这将为评估循证干预措施的效用提供有价值的信息。要实现 我的长期目标是成为一名独立科学家，在压力和昼夜节律研究之间转换 实验室和社区，该K01将在以下领域提供进一步的培训：1)标准化和 评估应激方案；2)高级统计培训，用于检查应激的时间顺序 3)突发心血管事件的病因、预防和心血管健康评估知识。

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.