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

项目3摘要 20多年前，早期生活应激(ELS)与成人发病的心血管疾病(CVD)密切相关，但 仍然是一个被低估的心血管疾病风险因素。超过一半的美国成年人报告有ELS暴露，如 童年时期的家庭功能障碍、虐待或疏忽。我们的出版物显示，患有ELS的成年人有 增加未来心血管疾病风险的指标，包括随意血压(BP)、脉搏波速度(PWV)和 循环中的促炎因子。项目1和2显示ELS的动物模型有高血压 致敏、交感神经驱动增强、血管功能障碍和促炎因子的激活 巨噬细胞是心血管疾病风险的已知驱动因素。我们对ELS如何影响指标的认识存在差距 对于青春期未来的心血管疾病风险，以及ELS动物模型中相同的途径是否相关 有心血管疾病风险的人。因此，项目3的主要重点是解决以下方面的差距 青春期确定ELS相关心血管风险的关键临床特征和分子途径，与 有可能指导早期干预以预防或减轻心血管疾病。我们的初步数据进一步支持 项目3的理论基础表明，患有ELS的青少年血管僵硬和可步行能力增加 舒张压、血浆促炎代谢物模式和基因甲基化模式 循环中的单核细胞。项目3的中心假设是ELS促进血管僵硬和 青少年通过循环代谢物的促炎性重编程引起的动态血压异常 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项 阿拉巴马州不同种族青春期女孩和男孩的组学分析。目标1将检验假设 暴露于ELS的青少年将会增加血管僵硬和动态血压。协作性 实验还将比较青少年(项目3)和成年人(项目3)心血管疾病风险指标的差异 4)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力的替代指标。 Aim 2将验证ELS与血浆代谢物中的促炎模式相关的假设 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 酸(SCFA)和HDAC9和NOX2基因甲基化，与项目1和2中ELS的动物模型相同。 我们将把我们在青少年中的代谢组和甲基组数据与互补的微生物组结合起来， 项目4中成人的代谢组和转录组数据，以发现连接ELs的新的多组体途径 从青春期到成年期都有血管功能障碍。项目3在概念上是创新的，通过测试我们的 青少年的中心假说有助于确定未来预防ELS相关干预研究的目标 心血管疾病。拟议的工作具有翻译相关性，通过应用项目1和项目1的基础科学发现 2(SCFA相关的血管功能障碍，促炎基因甲基化模式，并增加 同情的驱动力)来发展中心假设和目标。

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.