Early Life Stress-induced Reprogramming of Ambulatory Blood Pressure and Vascular Function in Adolescence

生命早期压力引起的青春期动态血压和血管功能的重编程

• 批准号: 10555127
• 负责人: Michael Edward Seifert
• 金额: $ 34.18万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555127
• 关键词: 19 year old; Address; Adolescence; Adolescent; Adult; Affect; Age; Alabama; Animal Model; Aorta; Basic Science; Biological Assay; Blood Pressure; Blood Vessels; Brain; CD14 gene; COVID-19; Cardiovascular Diseases; Cardiovascular system; Childhood; Clinic; Clinical; Collaborations; Complement; Cross-Sectional Studies; Data; Diastolic blood pressure; Early Intervention; Early identification; Enrollment; Epigenetic Process; Exposure to; Female Adolescents; Functional disorder; Future; Genes; HDAC9 gene; Heart Rate; Household; Human; Hypertension; Inflammatory; Intervention Studies; Intervention Trial; Knowledge; Link; Longevity; Macrophage; Macrophage Colony-Stimulating Factor; Male Adolescents; Methylation; Molecular; Mus; Outcome; Pathway interactions; Patient Self-Report; Pattern; Persons; Phenotype; Physiologic pulse; Pilot Projects; Plasma; Public Health; Publications; Reporting; Research; Research Design; Risk; Risk Factors; Role; Salivary; Sampling; Testing; Vascular Diseases; Vascular Endothelium; Volatile Fatty Acids; Work; blood pressure variability; cardiovascular disorder risk; cardiovascular risk factor; cohort; cytokine; data repository; early life stress; epigenome; experimental study; indexing; innovation; metabolome; methylation pattern; methylome; microbiome; monocyte; multiple omics; neglect; pandemic stress; poor health outcome; prevent; protective effect; protective factors; racial diversity; resilience; secondary analysis; synergism; therapeutic target; transcriptome

PROJECT 3 SUMMARY Early life stress (ELS) was strongly linked with adult-onset cardiovascular disease (CVD) over 20 years ago but remains an under-appreciated CVD risk factor. More than half of U.S. adults report ELS exposures such as household dysfunction, abuse, or neglect in childhood. Our publications have shown that adults with ELS have increased indicators for future CVD risk, including casual blood pressure (BP), pulse wave velocity (PWV), and circulating pro-inflammatory factors. Projects 1 and 2 show that animal models of ELS have hypertension sensitization, increased sympathetic drive, vascular dysfunction, and activation of pro-inflammatory macrophages that are known drivers of CVD risk. There are gaps in our knowledge of how ELS affects indicators for future CVD risk in adolescence, and whether the same pathways in animal models of ELS are associated with CVD risk in people. Therefore, the principal focus of Project 3 is to address these gaps during adolescence to identify critical clinical features and molecular pathways in ELS-associated CVD risk, with the potential to guide early interventions to prevent or mitigate CVD. Our preliminary data further support the rationale for Project 3, showing that adolescents with ELS have increased vascular stiffness and ambulatory diastolic BP along with pro-inflammatory metabolite patterns in plasma and gene methylation patterns in circulating monocytes. The central hypothesis of Project 3 is that ELS promotes vascular stiffness and abnormal ambulatory BP in adolescents through pro-inflammatory reprogramming of the circulating metabolome and monocyte epigenome. Our cross-sectional study design utilizes comprehensive cardiovascular and multi- omics profiling in racially diverse adolescent girls and boys in Alabama. Aim 1 will test the hypothesis that adolescents exposed to ELS will have increased vascular stiffness and ambulatory blood pressure. Collaborative experiments will also compare differences in CVD risk indicators in adolescents (Project 3) vs. adults (Project 4) and study heart rate and BP variability as surrogates for increased sympathetic drive along with Project 2. Aim 2 will test the hypothesis that ELS is associated with pro-inflammatory patterns in the plasma metabolome and monocyte epigenome in adolescents. Collaborative experiments will specifically focus on short chain fatty acids (SCFA) and methylation of HDAC9 and NOX2 genes as in animal models of ELS from Projects 1 and 2. We will integrate our metabolome and methylome data in adolescents with complementary microbiome, metabolome, and transcriptome data in adults from Project 4 to discover new multi-omic pathways that link ELS with vascular dysfunction from adolescence to adulthood. Project 3 is conceptually innovative by testing our central hypothesis in adolescents to help identify targets for future intervention studies to prevent ELS-associated CVD. The proposed work has translational relevance by applying basic science discoveries from Projects 1 and 2 (SCFA-associated vascular dysfunction, pro-inflammatory gene methylation patterns, and increased sympathetic drive) to develop the central hypothesis and aims.

项目 3 摘要 20 多年前，早期生活压力 (ELS) 与成人发病的心血管疾病 (CVD) 密切相关，但 仍然是一个未被充分认识的 CVD 危险因素。超过一半的美国成年人报告了 ELS 暴露，例如 童年时期的家庭功能障碍、虐待或忽视。我们的出版物表明，患有 ELS 的成年人 增加未来 CVD 风险的指标，包括血压 (BP)、脉搏波速度 (PWV) 和 循环促炎因子。项目1和2显示ELS动物模型患有高血压 致敏、交感神经驱动增强、血管功能障碍和促炎物质激活 巨噬细胞是已知的 CVD 风险驱动因素。我们对 ELS 如何影响指标的了解存在差距 青春期未来 CVD 风险，以及 ELS 动物模型中的相同途径是否相关 有CVD风险的人。因此，项目 3 的主要重点是解决这些差距 青春期以确定 ELS 相关 CVD 风险的关键临床特征和分子途径， 指导早期干预措施预防或减轻 CVD 的潜力。我们的初步数据进一步支持了 项目 3 的基本原理，表明患有 ELS 的青少年的血管硬度和动态能力有所增加 舒张压以及血浆中的促炎代谢模式和基因甲基化模式 循环单核细胞。项目 3 的中心假设是 ELS 促进血管僵硬度 通过循环代谢组的促炎症重编程导致青少年动态血压异常 和单核细胞表观基因组。我们的横断面研究设计利用了全面的心血管和多因素 阿拉巴马州不同种族青少年女孩和男孩的组学分析。目标 1 将检验以下假设： 接触 ELS 的青少年会增加血管硬度和动态血压。协作性 实验还将比较青少年（项目 3）与成人（项目 4) 并与项目 2 一起研究心率和血压变异性作为增加交感神经驱动的替代指标。 目标 2 将检验 ELS 与血浆代谢组中促炎症模式相关的假设 和青少年的单核细胞表观基因组。合作实验将特别关注短链脂肪 项目 1 和 2 的 ELS 动物模型中的 HDAC9 和 NOX2 基因的酸 (SCFA) 以及甲基化。 我们将把青少年的代谢组和甲基化组数据与互补的微生物组整合起来， 项目 4 中成人的代谢组和转录组数据，以发现连接 ELS 的新多组学途径 从青春期到成年都有血管功能障碍。项目 3 在概念上是创新的，通过测试我们的 青少年的中心假设有助于确定未来干预研究的目标，以预防 ELS 相关的 化学气相沉积。通过应用项目 1 和 1 的基础科学发现，拟议的工作具有转化相关性 2（SCFA 相关血管功能障碍、促炎基因甲基化模式以及增加 同情驱动力）来发展中心假设和目标。