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 早期生活压力（EL）与20年前的成人心血管疾病（CVD）密切相关，但 仍然是一个不受欢迎的CVD风险因素。超过一半的美国成年人报告了EL的暴露，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，具有EL的成年人有 增加未来CVD风险的指标，包括休闲血压（BP），脉搏波速度（PWV）和 循环促炎因子。项目1和2表明，EL的动物模型患有高血压 致敏，交感神经驱动力增加，血管功能障碍和促炎性激活 巨噬细胞是CVD风险的已知驱动因素。我们对ELS如何影响指标的知识存在差距 对于未来的CVD风险，青春期以及EL动物模型中相同的途径是否相关 有人民的CVD风险。因此，项目3的主要重点是解决这些差距 青春期以与ELS相关的CVD风险中的关键临床特征和分子途径，与 潜力指导早期干预措施以预防或减轻CVD。我们的初步数据进一步支持 项目3的理由，表明具有EL的青少年具有增加的血管僵硬和卧床 舒张性BP以及血浆中的促炎性代谢物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促进了血管刚度和 通过循环代谢组的促炎性重编程，青少年的非卧床BP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 在阿拉巴马州种族多样化的青少年女孩和男孩中的OMICS分析。 AIM 1将检验以下假设 暴露于ELS的青少年将增加血管僵硬和卧床血压。协作 实验还将比较青少年中CVD风险指标的差异（项目3）与成人（项目 4）研究心率和BP的变异性作为替代的替代性，以及与项目2一起增加交感神经驱动器。 AIM 2将检验以下假设：ELS与血浆代谢组中的促炎模式有关 和青少年的单核细胞表观基因组。协作实验将特别关注短链脂肪 酸（SCFA）和HDAC9和NOX2基因的甲基化与项目1和2的EL动物模型一样。 我们将在具有互补微生物组的青少年中整合我们的代谢组和甲基化数据 来自项目4的成年人的代谢组和转录组数据，以发现新的多摩变途径 从青春期到成年的血管功能障碍。通过测试我们的项目3是概念上创新的 青少年的中心假设，以帮助确定未来干预研究的目标，以防止EL相关 CVD。拟议的工作通过应用项目1和 2（与SCFA相关的血管功能障碍，促炎基因甲基化模式和增加 同情驱动器）发展中心假设和目标。