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

儿童社会决定因素与青少年亚临床心血管疾病之间关联的微生物学机制

• 批准号: 10425095
• 负责人: Amanda K Marma
• 金额: $ 7.87万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425095
• 关键词: Adult; Age; American Heart Association; Ancillary Study; Area; Atherosclerosis; Behavioral; Biological; Birth; Butyrates; Cardiovascular Diseases; Carotid Arteries; Child Welfare; Childhood; Cities; DNA; DNA Methylation; Data; Development; Diet; Disease; Dose; Economic Factors; Enrollment; Environment; Epigenetic Process; Etiology; Exposure to; Family; Family Study; Feces; Funding; Future; Genotype; Gnotobiotic; Goals; Health; Health behavior; Housing; Human Microbiome; Image; Immigrant; Immune; Immune System Diseases; Infant; Intervention; Investigation; Life; Life Cycle Stages; Link; Literature; Long-Term Effects; Low income; Measures; Mediator of activation protein; Mental Depression; Metabolic Pathway; Metabolic dysfunction; Metabolism; Metagenomics; National Heart, Lung, and Blood Institute; National Institute of Child Health and Human Development; Newborn Infant; Outcome Study; Parents; Participant; Pathway interactions; Predisposition; Premature Mortality; Psychological Factors; Psychosocial Stress; Publishing; Research; Resistance; Risk Factors; Role; Science; Shotguns; Skin; Stress; Testing; United States National Institutes of Health; Unmarried; Youth; base; biobank; biological systems; cardiometabolism; cardiovascular disorder risk; cardiovascular risk factor; carotid intima-media thickness; design; disadvantaged population; disease phenotype; early life exposure; ethnic minority; experimental study; food insecurity; genome-wide; gut microbiome; gut microbiota; health disparity; immune function; immunoregulation; lower income families; microbial; microbiome; microbiome research; microbiota; mortality; mouse model; offspring; perceived stress; premature; psychologic; psychosocial; racial and ethnic; repository; resilience; response; social; social adversity; social determinants; social factors; social health determinants; sociodemographic group; socioeconomics; stool sample; stressor; young adult

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.

项目概要/摘要 在当代青年中，童年时期接触不良健康社会决定因素 (SDoH) 的现象非常普遍 并且与成人心血管疾病（CVD）发病率呈剂量依赖性相关。代谢和免疫 人们认为其中涉及功能障碍，但关于 SDoH 如何“深入皮肤”，仍然存在许多问题。 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 关联和相关差异，但该领域的研究很少。小型研究表明肠道 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，实验数据证明了因果关系 微生物组对宿主免疫功能、代谢和动脉粥样硬化的影响。然而，缺乏全面的数据 弱势群体中的 SDoH、微生物组和 CVD 表型是理解的关键障碍 潜在的联系。我们的长期目标是制定策略，减轻 SDoH 相关 CVD 的负担 弱势群体。当前提案的目标是建立一个生物样本库并生成 近期 R01 提案的试点和可行性数据，我们将在其中全面评估 年轻成人早期生命 SDoH、肠道微生物组和 CVD 风险指标之间的关联 检查限生小鼠模型中的因果机制。我们建议对超过 1000 名年轻人进行辅助研究 脆弱家庭研究（FFS）中的成年人。 FFS 于 1998 年至 2000 年间在美国大城市登记了新生儿，其中 对未婚、少数种族/族裔、移民和低收入父母所生婴儿的过度抽样。 已收集出生时和 1 岁、3 岁、 5、9 和 15 岁，以及 9 岁和 15 岁的基因型和全基因组 DNA 甲基化。 NHLBI- 22 岁时接受资助的 (R01 HL149869) 检查将包括类似的措施以及详细的 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R03，我们建议 建立 FFS 参与者的肠道微生物库，包括用于鸟枪法宏基因组的粪便 DNA 分析和新鲜粪便样本进行无菌实验，并通过 以下具体目标：(1) 确定生命早期 SDoH 与年轻成人肠道微生物群的关联，以及 (2) 识别与年轻成人亚临床 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，为后续 R01 提案的设计提供信息。生物样本 拟议项目产生的数据将直接支持 PI 向独立的成功过渡 她的研究建立在 K23 资助的基础上，研究肠道微生物组是生命早期 CVD 风险的一个因素。这 随后的 R01 中提出的科学将大大促进我们对 暴露于社会逆境后肠道微生物群在早期心血管疾病发展中的作用。