Temporal Genomics Mechanisms Underlying Disease and Aging

项目摘要 早期生活中的逆境可以“深入到皮肤下”，并编程生物系统，这反过来会增加患上 晚年的身体和心理健康问题。然而，人们对早年的逆境如何转化为 面对急性应激源时的动态细胞反应。这项提案的目标是确定可能的 涉及到年轻人的机制。在具有独特响应性和可访问性的组织中(外周血 ，我们将通过RNA测序来测量应激诱导的基因表达变化 超过4小时的窗口后测试，以及炎性细胞因子(C反应蛋白、IL-6和肿瘤坏死因子-α)和外周血单核细胞 端粒酶活性和端粒长度。PBMC通过调节对刺激的反应表现出显著的灵活性 基因以一种短暂的方式表达。存在快速(例如，30分钟至4小时)PBMC基因的经验证据 人类对各种应激刺激的反应中的表达激活。端粒系统已经被 与发病率和早期死亡率以及早期逆境有关。心理健康症状可能会影响 神经内分泌和自主神经系统的进程和反应性，然而，对于是否抑郁知之甚少。 焦虑症状可以预测急性应激后差异基因表达的激活。建议数 这项研究将率先推进对压力诱导的基因表达变化的理解，因为这是有节制的 受既往逆境、端粒长度缩短和心理健康症状的影响。 Aim 1将在受试者内部设计中，测试暴露在早期生活逆境中的个体是否表现出 基因表达和蛋白质水平(细胞因子和端粒酶)的失调变化 确定的实验室应激源(Trier社会压力测试)，与间隔一周的无应激条件进行比较， 并与没有经历过早期逆境的人进行比较。我们预测了转录的快速变化， 尤其是糖皮质激素信号和对逆境的保守转录反应(CTRA) 路径，通过暴露在逆境中而缓和。目标2将在基线时增加端粒长度的测量，作为 检测端粒长度是否能预测差异表达基因的激活。 对急性压力的反应。我们预测，基线时较短的端粒长度将与较大的 端粒酶活性以及端粒相关的转录变化、衰老和细胞凋亡 小路。目标3将研究抑郁和焦虑症状是否与调节失调有关 应激反应中基因表达和蛋白质水平的变化。我们预测抑郁症的程度会更高 焦虑将与糖皮质激素信号、代谢和CTRA基因的失调有关。 这项创新的研究首次将动态RNA测序方法与多个水平的 同时进行分析，包括炎性细胞因子、端粒长度、端粒酶活性和精神- 相同个体的健康症状，由于早期的逆境而有所缓解。这一综合方法将 提供一个机会来识别动态转录信号，以响应可能发出信号的压力 与早年逆境相关的疾病风险的特定特征，例如，在乳腺癌和白血病中可以看到 癌症。方法论上的进步是研究是严格的受试者内实验设计，而 以前的大多数研究都是观察性和横断性的；对基因的重复测量 使用强大的RNA测序方法在~5小时内表达将使细胞路径测试成为可能 与早期逆境和心理健康疾病的病因学有关；重复的数据共享 全转录信息将作为一个发现、透明和可重复性的平台；测试 早期逆境、端粒长度和心理健康症状的调节效应将使我们能够探索 生物系统的潜在编程；以及端粒酶活性的测量使压力测试- 诱导基因表达的变化与细胞的生存机制有关。通过测试动态应力引起的 年轻人早期逆境的后遗症研究将确定在以下过程中起作用的途径 疾病易感性和加速衰老。这一发现将对翻译科学产生重要影响。 和基础生物学。例如，是特定类型的干预(例如，认知行为、正念 冥想、药理)通过转录改变来调节？这些干预措施能逆转吗？ 转录模式是否与应激相关疾病有关？也许最重要的是， 干预措施是否量身定做，以匹配个人体内运行的特定细胞过程？

Project Summary Early-life adversity can `get under the skin' and program biological systems, which in turn increases risk for later-life physical and mental-health problems. However, little is known how early-life adversity translates to dynamic cellular responses when facing acute stressors. The goal of this proposal is to identify possible mechanisms involved in young adults. In a uniquely responsive and accessible tissue (peripheral blood mononuclear cells, PBMC), we will measure stress-induced gene expression changes via RNA sequencing over a 4-hour window post-test, as well as inflammatory cytokines (CRP, IL-6, and TNF-α), and PBMC telomerase activity and telomere length. PBMCs show remarkable flexibility in response to stimuli by regulating gene expression in a transient manner. Empirical evidence exist for rapid (e.g., 30 min to 4 hours) PBMC gene expression activation in response to various stressful stimuli in humans. The telomere system has been associated with morbidity and early mortality, as well as early adversity. Mental-health symptoms can influence the course and reactivity of neuroendocrine and autonomic systems, however little is known whether depressive and anxiety symptoms can predict differential gene expression activation following acute stress. The proposed research will be the first to advance understanding of stress-induced gene expression changes, as moderated by previous adversity, shorter telomere length and mental health symptoms. Aim 1 will test, in a within-subjects design, whether individuals exposed to early-life adversity show dysregulated changes in gene expression and protein levels (cytokines and telomerase) in response to a well- established laboratory stressor (Trier Social Stress Test), compared with a no-stress condition one week apart, and compared with individuals without exposure to early adversity. We predict rapid transcriptomic changes, specifically in glucocorticoid signaling and the conserved transcriptional response to adversity (CTRA) pathways, moderated by exposure to adversity. Aim 2 will add a measure of telomere length at baseline, as a marker of `exhausted cells', to test whether telomere length can predict differential gene expression activation in response to acute stress. We predict that shorter telomere length at baseline will be associated with greater telomerase activity, as well as transcriptomic changes in telomere-related, senescence and apoptosis pathways. Aim 3 will examine whether depressive and anxiety symptoms are associated with dysregulated changes in gene expression and protein levels in response to stress. We predict higher levels of depression and anxiety will be associated with dysregulation of glucocorticoid signaling, metabolic and CTRA genes. This innovative study is the first to combine a dynamic RNA sequencing approach with multiple levels of analysis simultaneously, including inflammatory cytokines, telomere length, telomerase activity and mental- health symptoms in the same individuals, as moderated by early adversity. This integrated approach will provide an opportunity to identify dynamic transcriptomic signatures in response to stress that could signal specific profiles of disease risk associated with early-life adversity, as seen, for example, in breast and leukemia cancers. Methodological advances are that the study is a rigorous within-subject experimental design whereas most previous studies have been observational and cross-sectional; repeated measurements of gene expression over ~5 hours using the powerful RNA sequencing approach will enable tests of cellular pathways that are implicated in the etiology of early adversity and mental-health diseases; the data sharing of repeated whole-transcriptomic information will serve as a platform for discovery, transparency and reproducibility; testing moderation effects of early adversity, telomere length and mental-health symptoms will enable us to explore potential programming of biological systems; and measures of telomerase activity enable tests of stress- induced gene expression changes with cellular survival mechanisms. By testing the dynamic stress-induced sequelae of early adversity in young adults the research will identify pathways playing a downstream role in disease susceptibility and accelerated aging. Findings will have important implications for translational science and basic biology. For example, are specific type of interventions (e.g., cognitive-behavioral, mindfulness meditation, pharmacological) mediated through transcriptomic changes? Can these interventions reverse transcriptional patterns implicated in stress-related disorders? And perhaps most importantly, can the interventions be tailored to match the specific cellular processes operating within an individual?