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

项目总结/摘要 儿童期暴露于健康的不良社会决定因素（SDoH）在当代青年中非常普遍 并且以剂量依赖性方式与成人心血管疾病（CVD）发病率相关。代谢和免疫 功能障碍被认为是参与，但许多问题仍然是如何SDoH进入"皮肤下“， 激活导致CVD的生物途径。人类微生物组可能是SDoH-CVD的关键介质 协会和相关的差距，但在这方面的研究是稀疏的。小型研究表明， 微生物组因社会经济水平而异，并且可以通过住房环境，社会 连通性和社会心理压力另外，实验数据表明， 微生物组在宿主免疫功能、代谢和动脉粥样硬化中的作用。然而，由于缺乏全面数据， 弱势群体中的SDoH、微生物组和CVD表型是理解的关键障碍 潜在链接我们的长期目标是制定策略，以减少SDoH相关CVD的负担， 弱势群体。目前提案的目标是建立一个生物储存库， 近期R 01提案的试点和可行性数据，我们将全面评估 年轻人早期生活SDoH，肠道微生物组和CVD风险指标之间的关联， 在一个gnotobiotic小鼠模型中研究因果机制。我们建议对>1000名年轻人进行辅助研究 脆弱家庭研究（FFS）1998-2000年，FFS在美国大城市登记了新生儿， 对未婚、种族/少数民族、移民和低收入父母所生婴儿的过度抽样。 全面，详细的SDoH，心理和行为数据已收集在出生和年龄1，3， 5岁、9岁和15岁，以及9岁和15岁时的基因型和全基因组DNA甲基化。NHLBI- 22岁时的资助（R 01 HL 149869）检查将包括类似的测量加上详细的CVD风险因素 数据和最先进的颈动脉成像来检测早期动脉粥样硬化。对于当前的R 03，我们建议 从FFS参与者中建立肠道微生物组库，包括用于鸟枪宏基因组学的粪便DNA， 分析和新鲜粪便样本进行无菌实验，并通过 以下具体目的：（1）确定早期生活SDoH与成年肠道微生物群的关联，以及（2） 确定与成年人亚临床CVD、CVD危险因素和表观遗传相关的肠道微生物群变量 年龄，在N=95 FFS参与者的子集中，以通知后续R 01提案的设计。生物标本 从拟议项目产生的数据将直接支持PI成功过渡到独立 基金，建立在她的K23资助的肠道微生物组的研究作为早期生命中CVD风险的贡献者。的 在随后的R 01中提出的科学将大大促进我们对 肠道微生物组在暴露于社会逆境后早期CVD发展中的作用

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.