Temporal Genomics Mechanisms Underlying Disease and Aging

疾病和衰老的时间基因组学机制

• 批准号: 9751692
• 负责人: Idan Shalev
• 金额: $ 23.79万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2021-05-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751692
• 关键词: Acute; Address; Affect; Age; Aging; Anxiety; Apoptosis; Apoptotic; Basic Science; Behavioral; Bioinformatics; Biological; Biological Markers; Biology; Blood Pressure; Breast; CD8B1 gene; Cell Aging; Cell physiology; Cells; Clinical; Clinical Treatment; Cognitive; DNA Damage; Data; Development; Disease; Disease susceptibility; Elderly; Epigenetic Process; Etiology; Experimental Designs; Exposure to; Failure; Future; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Genomics; Glucocorticoids; Goals; Health; Heart Rate; Hour; Human; Hydrocortisone; Immune; Immunologics; Individual; Individual Differences; Inflammatory; Interleukin-6; Intervention; Intervention Studies; Knowledge; Laboratories; Lead; Length; Life; Link; Long-Term Effects; Malignant Neoplasms; Measurement; Measures; Mediating; Mediator of activation protein; Mental Depression; Mental Health; Metabolic; Methodology; Modeling; Morbidity - disease rate; Neurosecretory Systems; Outcome; Participant; Pathway interactions; Patient Self-Report; Pattern; Peripheral Blood Mononuclear Cell; Pharmacological Treatment; Pharmacology; Physiological; Play; Predisposition; Prevention; Process; Proliferating; Proteins; Randomized; Reproducibility; Research; Research Design; Resources; Reverse Transcription; Risk; Role; Salivary; Sample Size; Sampling; Signal Transduction; Skin; Standardization; Stimulus; Stress; Stress Tests; Stressful Event; Survivors; Symptoms; System; TNF gene; Telomerase; Testing; Tissue-Specific Gene Expression; Tissues; Transcriptional Regulation; Translating; Translational Research; Treatment Efficacy; Trier Social Stress Test; Variant; Woman; Work; acute stress; adverse event risk; anxiety symptoms; associated symptom; base; biological adaptation to stress; biological systems; clinical practice; cytokine; data sharing; depressive symptoms; design; differential expression; disorder risk; early life adversity; exhaust; flexibility; gender difference; genome wide methylation; in vivo; innovation; instrument; leukemia; longitudinal analysis; men; mental health related disorder; mindfulness meditation; monocyte; mortality; physical conditioning; prenatal; programs; psychologic; public health relevance; recruit; response; screening; senescence; stress related disorder; stressor; telomere; transcriptome sequencing; transcriptomics; young adult; young man

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?

项目概要 早年的逆境可能会“深入人心”并对生物系统进行编程，从而增加了患此病的风险。 然而，人们很少知道早年的逆境如何转化为晚年的身体和心理健康问题。 面对急性应激源时的动态细胞反应该提案的目标是确定可能的情况。 涉及年轻人的机制。 单核细胞，PBMC），我们将通过 RNA 测序测量应激诱导的基因表达变化 测试后 4 小时内的窗口期，以及炎症细胞因子（CRP、IL-6 和 TNF-α）和 PBMC 端粒酶活性和端粒长度通过调节而表现出显着的响应刺激的灵活性。 存在快速（例如 30 分钟至 4 小时）PBMC 基因表达的经验证据。 人类端粒系统响应各种压力刺激而表达激活。 与发病率和早期死亡率以及早期逆境症状相关。 神经内分泌和自主系统的过程和反应性，但人们对抑郁症是否 焦虑症状可以预测急性应激后差异基因表达激活。 研究将是第一个推进对压力诱导的基因表达变化的理解的研究 以前的逆境、较短的端粒长度和心理健康症状。 目标 1 将在受试者内部设计中测试暴露于早年逆境的个人是否表现出 基因表达和蛋白质水平（细胞因子和端粒酶）的失调变化，以响应良好的 建立实验室压力源（特里尔社会压力测试），与相隔一周的无压力条件进行比较， 与没有经历过早期逆境的个体相比，我们预测转录组会发生快速变化， 特别是在糖皮质激素信号传导和逆境保守转录反应 (CTRA) 方面 通过暴露于逆境来调节路径，目标 2 将在基线上添加端粒长度的测量，作为 “耗尽细胞”的标记，以测试端粒长度是否可以预测差异基因表达激活 我们预测基线端粒长度越短，与应激反应越大。 端粒酶活性，以及​​端粒相关、衰老和细胞凋亡的转录组变化 目标 3 将检查抑郁和焦虑症状是否与失调相关。 我们预测抑郁症的水平会更高。 焦虑与糖皮质激素信号、代谢和 CTRA 基因的失调有关。 这项创新研究首次将动态 RNA 测序方法与多水平的 RNA 测序相结合。 同时进行分析，包括炎症细胞因子、端粒长度、端粒酶活性和心理 这种综合方法将减轻同一个人的健康症状。 提供了一个机会来识别动态转录组特征，以响应可能发出信号的压力 与早年不幸相关的疾病风险的具体概况，例如乳腺癌和白血病 方法学上的进步在于该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面的基因重复测量； 使用强大的 RNA 测序方法进行约 5 小时的表达将能够测试细胞通路 与早期逆境和精神健康疾病的病因学有关的重复数据共享； 全转录组信息将作为发现、透明度和可重复性测试的平台； 早期逆境、端粒长度和心理健康症状的调节作用将使我们能够探索 生物系统的潜在编程；端粒酶活性的测量使得压力测试成为可能 通过测试动态应激诱导的基因表达变化与细胞生存机制。 该研究将确定在年轻人早期逆境的后遗症中发挥下游作用的途径 疾病易感性和加速衰老的研究结果将对转化科学产生重要影响。 例如，特定类型的干预措施（例如认知行为、正念） 通过转录组变化介导的冥想、药理学）这些干预措施可以逆转吗？ 也许最重要的是，转录模式是否与压力相关疾病有关？ 干预措施是否需要根据个体体内特定的细胞过程进行定制？