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; 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?

项目摘要 早期生活广告可以“在皮肤下”和程序生物系统，从而增加了 后期生活和心理健康问题。但是，鲜为人知的早期广告如何转化为 面对急性应激源时动态细胞反应。该提议的目的是确定可能 年轻人涉及的机制。在独特的响应式且可及的组织中（外周血） 单核细胞，PBMC），我们将通过RNA测序测量应力诱导的基因表达变化 测试后4小时，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，PBMC在响应刺激方面表现出显着的灵活性 基因表达以瞬态方式。有经验证据存在于快速（例如30分钟至4小时）PBMC基因 对人类各种压力刺激的反应激活。端粒系统已经 与发病率和早期死亡率以及早期广告有关。心理健康症状会影响 神经内分泌和自主系统的课程和反应性，多么了解抑郁症 焦虑症状和焦虑症状可以预测急性应激后差异基因表达激活。提议 随着调节 通过以前的广告，端粒长度和心理健康症状。 AIM 1将在受试者内设计中测试个人是否暴露于早期广告展览会 对良好的响应 建立的实验室压力源（Trier社会压力测试），相比之下，相比有一周的无压力状况 与没有早期广告的个人相比。我们预测快速转录组变化， 特别是糖皮质激素信号传导和对广告的配置转录响应（CTRA） 途径，通过暴露于广告而节。 AIM 2将在基线时增加端粒长度的度量，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 对急性应力的反应。我们预测基线时较短的端粒长度将与更大的相关 端粒酶活性以及端粒相关，感应和凋亡的转录组变化 途径。 AIM 3将检查抑郁症和焦虑症状是否与失调有关 基因表达和蛋白质水平的变化响应压力。我们预测抑郁症的水平更高 动画将与糖皮质激素信号，代谢和CTRA基因的失调有关。 这项创新的研究是第一个将动态RNA测序方法与多个级别的 简单地分析，包括炎性细胞因子，端粒长度，端粒酶活性和精神 同一个人的健康症状，如早期广告所带来的。这种综合方法将 提供一个机会，以响应可能发出信号的压力来识别动态转录组特征 与早期广告相关的疾病风险的特定概况，例如在乳房和白血病中所见 癌症。方法论上的进步是，该研究是严格的受试者内实验设计 以前的大多数研究都是观察性的和横断面的。重复测量基因 使用强大的RNA测序方法表达在〜5小时以上，将实现细胞途径的测试 早期广告和心理健康疾病的病因中暗示了这一点；重复的数据共享 全转录组信息将作为发现，透明和可重复性的平台；测试 早期广告，端粒长度和心理健康症状的适度影响将使我们能够探索 生物系统的潜在编程；端粒酶活性的度量可以测试应力 - 诱导的基因表达随细胞存活机制而变化。通过测试动态应力诱导的 年轻人早期广告的后遗症研究将确定途径在下游中扮演的角色 疾病的敏感性和加速衰老。调查结果将对转化科学具有重要意义 和基本生物学。例如，是特定类型的干预措施（例如，认知行为，正念 冥想，通过转录组变化介导的药物？这些干预措施可以逆转吗 在与压力有关的疾病中实施的转录模式？也许最重要的是，可以 量身定制干预措施以匹配个人内部运行的特定蜂窝过程？