Microbiomic Mechanisms of Association between Childhood Social Determinants and Young-Adult Subclinical CVD

项目摘要/摘要 儿童时期接触不良的社会健康决定因素(SDoH)在当代青年中非常普遍 并且与成人心血管疾病(CVD)的发病率呈剂量依赖关系。代谢和免疫 功能障碍被认为与此有关，但SDoH是如何“潜伏”到 激活导致心血管疾病的生物通路。人的微生物群可能是SDoH-CVD的关键介质 在这方面的研究很少，但这方面的研究还很少。小规模的研究表明，肠道 微生物群在不同的社会经济水平上有所不同，并可以受到住房环境、社会环境和社会环境的影响 连通性和心理社会压力。另外，实验数据显示了 微生物组与宿主免疫功能、代谢和动脉粥样硬化的关系。然而，缺乏全面的数据关于 弱势人群中的SDoH、微生物组和心血管疾病表型是理解的关键障碍 潜在的链接。我们的长期目标是制定策略，减轻与SDoH相关的心血管疾病的负担 弱势群体。目前提议的目标是建立一个生物储存库并产生 近期R01提案的试点和可行性数据，其中我们将致力于全面评估 青壮年早期SDoH、肠道微生物群和心血管疾病风险指标之间的关系 在诺生菌小鼠模型中检查因果机制。我们建议对&gt；1000 Young进行一项辅助研究 脆弱家庭中的成年人研究(FFS)。1998年至2000年，FFS在美国大城市招收新生儿， 对未婚、少数族裔、移民和低收入父母所生婴儿进行过度抽样。 全面、详细的SDoH、心理和行为数据在出生时和1、3岁时收集到， 5岁、9岁和15岁，以及9岁和15岁时的基因和全基因组DNA甲基化。NHLBI- 资助(R01 HL149869)22岁的检查将包括类似的措施和详细的心血管疾病风险因素 数据和最先进的颈动脉成像，以检测早期动脉粥样硬化。对于目前的R03，我们建议 从FFS参与者建立肠道微生物群库，包括用于猎枪元基因组的粪便DNA 分析和新鲜粪便样本，以进行生理学实验，并通过 具体目标如下：(1)确定早期SDoH与青壮年肠道微生物区系的关系，以及(2) 确定与青年亚临床心血管疾病、心血管疾病危险因素和表观遗传学相关的肠道微生物区系变量 年龄，在N=95个FFS参与者的子集中，以告知设计随后的R01提案。生物有机磷农药 而拟议项目产生的数据将直接支持PI向独立的成功过渡 资金，建立在她K23资助的肠道微生物群研究的基础上，该研究是早期生命中心血管疾病风险的贡献者。这个 在随后的R01中提出的科学将极大地促进我们对 暴露在社会逆境中的早期心血管疾病发展中的肠道微生物群。

PROJECT SUMMARY/ABSTRACT Childhood exposure to adverse social determinants of health (SDoH) is highly prevalent in contemporary youth and is linked in a dose-dependent manner with adult cardiovascular disease (CVD) rates. Metabolic and immune dysfunction are thought to be involved, but many questions remain as to how SDoH get `under the skin' to activate biological pathways leading to CVD. The human microbiome may be a key mediator of SDoH-CVD associations and related disparities, but research in this area is sparse. Small studies indicate that the gut microbiome varies across socioeconomic levels and can be modified by housing environments, social connectedness, and psychosocial stress. Separately, experimental data demonstrate causal roles for the microbiome in host immune function, metabolism, and atherosclerosis. However, lack of comprehensive data on SDoH, the microbiome, and CVD phenotypes in disadvantaged populations is a critical barrier to understanding potential links. Our long-term goal is to develop strategies to reduce the burden of SDoH-related CVD in disadvantaged populations. The objective of the current proposal is to establish a biorepository and generate pilot and feasibility data for a near-term R01 proposal in which we will aim to comprehensively assess associations between early-life SDoH, the gut microbiome, and CVD risk indicators in young adults and further examine causal mechanisms in a gnotobiotic mouse model. We propose an ancillary study of >1000 young adults in the Fragile Families Study (FFS). FFS enrolled newborns in large US cities from 1998-2000, with oversampling of infants born to unmarried, racial/ethnic minority, immigrant, and low-income parents. Comprehensive, detailed SDoH, psychological, and behavioral data have been collected at birth and ages 1, 3, 5, 9, and 15 years, as well as genotype and genome-wide DNA methylation at ages 9 and 15 years. The NHLBI- funded (R01 HL149869) examination at age 22 years will include similar measures plus detailed CVD risk factor data and state-of-the-art carotid artery imaging to detect early atherosclerosis. For the current R03, we propose to establish a gut microbiome repository from FFS participants, including stool DNA for shotgun metagenomic analysis and fresh stool samples for gnotobiotic experiments, and to generate preliminary data through the following Specific Aims: (1) Identify associations of early-life SDoH with the young-adult gut microbiota, and (2) Identify gut microbiota variables associated with young-adult subclinical CVD, CVD risk factors, and epigenetic age, in a subset of N=95 FFS participants, to inform design of the subsequent R01 proposal. The biospecimens and data resulting from the proposed project will directly support successful transition of the PI to independent funding, building on her K23-funded study of the gut microbiome as a contributor to CVD risk in early life. The science proposed in the subsequent R01 will substantially advance our understanding of the potential role of the gut microbiome in early CVD development after exposure to social adversity.