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

早期生活压力和保护因素对青年期血管功能和炎症的前瞻性影响

• 批准号: 10555128
• 负责人: Sylvie Mrug
• 金额: $ 36.51万
• 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/10555128
• 关键词: Adolescence; Adolescent; Adult; Adverse event; Age; Alabama; American; Animal Model; Animals; Aorta; Biological; Blood Pressure; Blood Vessels; C-reactive protein; Cardiovascular Diseases; Cardiovascular system; Child Rearing; Colony-Stimulating Factors; Data; Development; Diet; Evaluation; Evidence based intervention; Exposure to; Future; Gene Expression; Genetic Transcription; HDAC9 gene; Heart Rate; Histone Deacetylase; Human; Hypertension; Immune; Immune System Diseases; Immune system; Individual; Inflammation; Inflammatory; Interleukins; Intervention; Knowledge; Lead; Life Style; Link; Macrophage Colony-Stimulating Factor; Measures; Mediating; Mediation; Methylation; Modeling; Molecular; NADPH Oxidase; Outcome; Pathway interactions; Peripheral Blood Mononuclear Cell; Persons; Physical activity; Physiological; Psychosocial Factor; Risk Factors; Rodent; Rodent Model; Role; Stress; TNF gene; Testing; Time; Tissue-Specific Gene Expression; Up-Regulation; Vascular Diseases; Vascular System; Volatile Fatty Acids; blood pressure variability; cardiovascular disorder prevention; cardiovascular disorder risk; cardiovascular risk factor; cohort; critical developmental period; cytokine; early experience; early life stress; ethnic diversity; experience; gut microbiome; indexing; inflammatory marker; innovation; lifestyle factors; metabolome; metabolomics; methylome; microbiome; microbiome composition; multiple omics; novel; prevent; prospective; protective factors; resilience; synergism; transcriptome; young adult

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.

项目4摘要 早期生活压力(ELS)，定义为18岁之前发生的不良经历，是一种非常普遍的风险 心血管疾病(CVD)的因素。然而，制定有效的战略来预防 由于缺乏对生理途径的了解，暴露于ELS的个人的心血管疾病受到阻碍 潜在的ELS对心血管疾病的影响，以及可能缓解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 这与心血管疾病有关，包括组蛋白脱乙酰酶9(HDAC9)、NADPH氧化酶2的上调 (NOX2)和细胞因子；肠道微生物组多样性减少；短链脂肪酸减少 (SCFA)。这些途径共同通过免疫和血管的重新编程来诱发心血管疾病。 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 经历过ELS的人，以及他们是否会被饮食等生活方式因素改变， 在发育过程中进行体力活动和支持性的育儿。项目4将利用现有的、 来自阿拉巴马州伯明翰的1000名不同种族的成年人(29岁)，他们已经 以11岁、13岁、16岁和19岁的ELS和生活方式因素为特征，以检验ELS的假设 通过持续的促炎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)这些效应可能 在发育过程中受到保护性生活方式因素的影响。建议在29岁时进行的评估将 包括对成年后压力和生活方式因素的综合评估；血管功能；肠道 微生物组；单链脂肪酸；外周血单个核细胞(PBMC)转录组。来自所有五个国家的数据 跨越11岁到29岁的时间点将被整合以检验1)前瞻性地 成年后测量ELs与免疫和血管功能；2)这些关系是否 由肠道微生物组和PBMC转录组在成年期的促炎特征所介导；以及 3)饮食质量、体力活动和发育期间的支持性育儿方式是否会改变 ELS与成人肠道微生物组、PBMC转录组、免疫和血管的关系 功能。项目4在概念和翻译上都是创新的，通过测试特定的肠道微生物组和 在人类啮齿动物中发现的转录组途径。连同测试的项目3 青春期的互补代谢组和甲基组途径，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 在从青春期到青春期的关键发育时期。综合调查结果 由此，PPG将阐明与ELS诱导的心血管风险相关的致病途径和保护因素， 直接告知新的循证干预措施的发展。