Prospective Effects of Early Life Stress and Protective Factors on Vascular Function and Inflammation in Young Adulthood

项目4概要 早期生活压力（ELS），定义为发生在18岁之前的不良经历，是一种非常普遍的风险 心血管疾病（CVD）的危险因素。然而，制定有效的预防战略， 暴露于ELS的个体的CVD受到缺乏生理途径知识的阻碍 ELS对CVD的潜在影响，以及可能减轻这些影响的可塑性生活方式因素。 指导项目1和项目2的跨物种动物研究涉及特定的机制途径 将ELS与CVD联系起来，包括上调组蛋白脱乙酰酶9（HDAC 9）、NADPH氧化酶2 （NOX 2）和细胞因子;肠道微生物组多样性减少;短链脂肪酸减少 （SCFA）。总之，这些途径通过免疫和血管免疫系统的重编程诱导CVD。 ELS啮齿动物模型中的系统。然而，我们不知道这些途径是否会导致心血管疾病， 经历ELS的人，以及他们是否可以通过生活方式因素，如饮食， 身体活动和支持性的养育。项目4将利用现有的， 来自亚拉巴马伯明翰的1,000名成年人（年龄29岁）的种族多样化队列， 在11岁、13岁、16岁和19岁时对ELS和生活方式因素进行表征，以检验以下假设：1）ELS 通过持续的促炎性重编程诱导血管功能障碍和高血压， 肠道微生物组和外周血单核细胞转录组，以及2）这些影响可能 在发育过程中受到保护性生活方式因素的影响。29岁时的拟议评估将 包括对成年期压力和生活方式因素、血管功能、肠道 微生物组; SCFA;和外周血单核细胞（PBMC）转录组。所有五个数据 将整合11至29岁的时间点，以检验1）前瞻性 测量成年期ELS和免疫及血管功能; 2）这些关系是否 由成年期肠道微生物组和PBMC转录组的促炎谱介导;以及 3)无论是饮食质量，体育活动，和支持性的养育在发展过程中修改 ELS与成人肠道微生物组、PBMC转录组以及免疫和血管 功能项目4通过测试特定的肠道微生物组在概念上和实践上具有创新性， 在啮齿类动物中发现的转录组通路。与项目3一起， 补充代谢组和甲基化途径在青春期，这两个人类项目将指导 通过确定将ELS与血管功能障碍联系起来的新的多组学途径进行未来的机制研究 在从青春期到青年期的关键发展时期。综合调查结果 从这个PPG将阐明与ELS诱导的CVD风险相关的因果途径和保护因素， 直接为新的循证干预措施的发展提供信息。

PROJECT 4 SUMMARY Early life stress (ELS), defined as adverse experiences occurring before age 18, is a highly prevalent risk factor for cardiovascular disease (CVD). However, the development of effective strategies to prevent CVD in individuals exposed to ELS is hindered by lack of knowledge about physiological pathways underlying ELS effects on CVD, as well as malleable lifestyle factors that may mitigate these effects. Cross-species animal studies guiding Project 1 and Project 2 implicate specific mechanistic pathways that link ELS with CVD, including upregulation of histone deacetylase 9 (HDAC9), NADPH oxidase 2 (NOX2), and cytokines; reduced diversity in the gut microbiome; and reduction of short-chain fatty acids (SCFA). Together, these pathways induce CVD through reprogramming of the immune and vascular system in rodent models of ELS. However, we do not know whether these pathways lead to CVD in people who experienced ELS and whether they can be modified by lifestyle factors, such as diet, physical activity, and supportive parenting, during development. Project 4 will leverage an existing, ethnically diverse cohort of 1,000 adults (age 29) from Birmingham, Alabama, who have been characterized for ELS and lifestyle factors at ages 11, 13, 16, and 19, to test the hypotheses that 1) ELS induces vascular dysfunction and hypertension through sustained pro-inflammatory reprogramming of the gut microbiome and peripheral blood mononuclear cell transcriptome, and that 2) these effects may be modified by protective lifestyle factors during development. The proposed assessment at age 29 will include a comprehensive evaluation of stress and lifestyle factors in adulthood; vascular function; gut microbiome; SCFAs; and peripheral blood mononuclear cell (PBMC) transcriptome. Data from all five time points spanning ages 11 to 29 will be integrated to test 1) the relationship between prospectively measured ELS and immune and vascular function in adulthood; 2) whether these relationships are mediated by pro-inflammatory profiles of the gut microbiome and PBMC transcriptome in adulthood; and 3) whether diet quality, physical activity, and supportive parenting during development modify the relationships between ELS and adult gut microbiome, PBMC transcriptome, and immune and vascular function. Project 4 is conceptually and translationally innovative by testing specific gut microbiome and transcriptome pathways discovered in rodents in humans. Together with Project 3 which tests complementary metabolome and methylome pathways in adolescence, the two human projects will guide future mechanistic studies by identifying new multi-omic pathways that link ELS with vascular dysfunction during critical developmental periods spanning adolescence to young adulthood. The integrated findings from this PPG will elucidate causal pathways and protective factors related to ELS-induced CVD risk, directly informing the development of novel evidence-based interventions.