Psychobiological Regulation of Cell-Free Mitochondrial DNA in Human Saliva

项目摘要 线粒体是一种新兴的信号细胞器，参与压力调节和心理健康。识别 线粒体信号传导机制，包括分泌分子及其动态调节，将提供 必要的工具，以阐明其在应激病理生理学和其他疾病条件的作用。我们和其他人 最近已经确定，线粒体可以释放其自身的基因组作为无细胞线粒体DNA（cf. mtDNA），一种潜在的免疫原性分子，以不同的水平存在于人类血液中，特别是在 心理压力和精神病理学的状况。基于我们最近发现cf-mtDNA是 在人类唾液中可检测到，我们现在提出必要的基础研究，以建立唾液cf-mtDNA作为一种 对人类研究有用的标记物。根据我们的初步研究，这项为期两年的R21建议旨在i）绘制 健康成年绝经前妇女自然觉醒反应和cf-mtDNA的昼夜变化， 在男性中; ii）定义cf-mtDNA和关键类固醇激素之间的关联， 节律，包括皮质醇; iii）利用来自压力诱导方案的已经收集的唾液样品， 确定唾液cf-mtDNA是否可由急性社会评价性应激诱导;以及iv）唾液cf-mtDNA是否 反映血液水平或cf-mtDNA是否在这两种不同的生物流体中独立调节。在一起， 这些研究将确定唾液cf-mtDNA动态在时间尺度上的潜在性别差异，并提供 这是建立cf-mtDNA作为线粒体应激标记物的必要基础， 流行病学研究。

PROJECT SUMMARY Mitochondria are an emerging signaling organelle involved in stress regulation and mental health. Identifying mechanisms of mitochondrial signaling, including secreted molecules and their dynamic regulation, will provide the necessary tools to elucidate their role in stress pathophysiology and other disease conditions. We and others have recently established that mitochondria can release their own genome as cell-free mitochondrial DNA (cf- mtDNA), a potentially immunogenic molecule present in varying levels in human blood, particularly under conditions of psychological stress and psychopathology. Building on our recent discovery that cf-mtDNA is detectable in human saliva, we now propose foundational studies necessary to establish saliva cf-mtDNA as a useful marker for human research. Based on our preliminary studies, this 2-year R21 proposal aims to i) map the natural awakening response and diurnal variation of cf-mtDNA in healthy adult premenopausal women and in men; ii) define the association between cf-mtDNA and key steroid hormones with already well-defined diurnal rhythms, including cortisol; iii) leveraging already-collected saliva samples from a stress induction protocol, establish whether saliva cf-mtDNA is inducible by acute socioevaluative stress; and iv) whether saliva cf-mtDNA mirrors blood levels or whether cf-mtDNA is independently regulated in these two different biofluids. Together, these studies will establish potential sex differences in saliva cf-mtDNA dynamic across time scales, and provide the necessary basis to establish cf-mtDNA as a marker of mitochondrial stress in both mechanistic and epidemiological studies.