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.

项目摘要/摘要 儿童期暴露于健康的不利社会决定因素（SDOH）在当代青年中非常普遍 并以剂量依赖性的方式与成人心血管疾病（CVD）率相关。代谢和免疫 人们认为功能障碍涉及，但是关于SDOH如何“在皮肤下”的许多问题仍然存在 激活导致CVD的生物学途径。人类微生物组可能是SDOH-CVD的关键介体 关联和相关差异，但是在这一领域的研究很少。小型研究表明肠道 微生物组在社会经济层面各不相同，可以通过住房环境，社会来改变 联系和社会心理压力。另外，实验数据表明了因果关系 宿主免疫功能，代谢和动脉粥样硬化中的微生物组。但是，缺乏有关的全面数据 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，以减轻与SDOH相关的CVD负担 弱势群体。当前建议的目的是建立生物座席并产生 近期R01提案的飞行员和可行性数据，我们将全面评估 年轻人的早期SDOH，肠道微生物组和CVD风险指标之间的关联 检查gnotobiotic小鼠模型中的因果机制。我们提出了一项> 1000年轻的辅助研究 脆弱家庭中的成年人研究（FFS）。 FFS从1998 - 2000年开始在美国大城市招募新生儿， 未婚，种族/族裔少数民族，移民和低收入父母所生的婴儿过采样。 在出生和1，3，3，3岁时都收集了全面，详细的SDOH，心理和行为数据 5、9和15岁，以及9岁和15岁的基因组和全基因组DNA甲基化。 NHLBI- 22岁的资助（R01 HL149869）考试将包括类似措施以及详细的CVD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。对于当前R03，我们建议 从FFS参与者中建立肠道微生物组存储库，包括用于shot弹枪元基因组的粪便DNA 分析和新鲜的粪便样品，用于gnotobiotic实验，并通过 以下特定目的：（1）确定早期SDOH与年轻肠道菌群的关联，以及（2） 识别与年轻成年亚临床CVD，CVD风险因素和表观遗传因素相关的肠道菌群变量 年龄在n = 95 ffs参与者的子集中，以告知随后的R01提案的设计。生物测量 拟议项目产生的数据将直接支持PI的成功过渡 基于她的K23资助的肠道微生物组的研究，作为早期CVD风险的贡献。这 随后的R01中提出的科学将大大促进我们对 暴露于社会逆境后的早期CVD发展中的肠道微生物组。