BIOLOGICAL EMBEDDING OF SOCIAL DISADVANTAGE IN HUMAN STEM CELLS: IMPLICATIONS FOR HEALTH DISPARITIES

人类干细胞中社会劣势的生物嵌入：对健康差异的影响

基本信息

批准号：
10594741
负责人：
Kristen Elizabeth Boyle
金额：
$ 63.21万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-26 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594741
关键词：
Activities of Daily Living Address Adipocytes Adipose tissue Animals Back Basic Science Behavioral Biological Biological Phenomena Biology Birth Black race Body Composition Cell Culture System Cell Culture Techniques Cell Differentiation process Cell Line Cell physiology Cells Cellular biology Characteristics Child Clinical Investigator Collaborations Communities Coupled Data Densitometry Development Early Diagnosis Embryo Endocrine Ensure Epigenetic Process Ethnic Origin Exposure to Fatty acid glycerol esters Functional disorder Future Gene Expression Generations Genes Glucose Goals Health Hispanic Homeostasis Human Immune In Vitro Individual Inflammatory Insulin Investigation Knowledge Life Ligands Long-Term Effects Longevity Machine Learning Maternal Exposure Measures Mediating Mesenchymal Mesenchymal Stem Cells Metabolic Metabolic dysfunction Methods Mitochondria Molecular Mothers Nature Neonatal Newborn Infant Not Hispanic or Latino Obesity Outcome Participant Pathway interactions Peroxisome Proliferator-Activated Receptors Personal Satisfaction PhenX Toolkit Phenotype Physiology Population Pregnancy Prevention Process Proxy Public Health Publishing Race Recommendation Research Design Research Personnel Resolution Resource Sharing Risk Stress Stromal Cells Testing Time Tissue Sample Tissues Umbilical Cord Blood Umbilical cord structure United States National Institutes of Health Variant World Health Organization base biobank body system burden of illness cell type cellular targeting clinical phenotype clinically relevant clinically significant cohort disorder risk experimental study fetal health disparity health disparity populations human stem cells imprint in utero in vivo innovation insulin regulation insulin sensitivity interest metabolic phenotype newborn adiposity novel offspring personalized intervention personalized predictions predictive modeling primary outcome psychosocial recruit repository sex social disadvantage stem stem cell biology stem cell function stem cell population stem cells stromal progenitor translational approach transmission process

项目摘要

ABSTRACT Exposure to social disadvantage is the most salient determinant of population health disparities. Although sub- stantial progress had been made in understanding how social disadvantage becomes biologically embedded, crucial knowledge gaps remain. Biological embedding has been described primarily at the level of differentiated cell types and tissues. Based on the consideration that a) social disadvantage’s long-term effects extend well beyond the lifespan of differentiated cells, whose replenishment occurs only from stem/progenitor cells, and b) can be perpetuated across generations, we advance the novel hypothesis that the origins of health disparities may extend all the way down to the level of stem cells, and specifically to the effects of maternal social disadvantage exposure on offspring stem cells during embryonic/fetal life. Our proposed study will focus on disparities between Hispanic, non-Hispanic Black, and non-Hispanic White mothers and their newborns in obesity and metabolic phenotypes; on mesenchymal progenitor/stromal cells (MSCs) and MSC- derived adipocytes as the stem and differentiated cells of interest; on mitochondrial function, adipogenic propensity/activity and insulin sensitivity as the key intracellular processes of importance; on newborn adipose tissue mass and glucose-insulin regulation as the outcomes of significance; and on maternal-fetal gestational biology as the proximate transmission pathway. We will conduct this study in a cohort of N=240 child-mother dyads; isolate and culture fetal MSCs from newborn cord tissue; perform high-resolution cellular experiments; and characterize neonatal phenotypes in vitro in MSC-derived adipoctyes, and in vivo using whole body densitometry. Aim 1 will test the hypothesis that maternal exposure to social disadvantage is associated with newborn mesenchymal stem cell characteristics, i.e., reduced mitochondrial efficiency, increased adipogenic propensity, and reduced insulin sensitivity. Aim 2 will test the hypothesis that variation in ma- ternal and fetal gestational biology (composite measures of endocrine, immune/inflammatory, and metabolic ligands) mediates the effects of social disadvantage on newborn mesenchymal stem cells. Aim 3 will establish the clinical significance of variation in MSC characteristics for neonatal obesity-related phenotypes at the a) cellular level (MSC- derived adipocyte size and fat content; mitochondrial function; adipogenic activity), and b) whole-body level (percent fat mass and systemic insulin sensitivity). Aim 4 (exploratory) will elucidate potentially modifiable maternal psychosocial and behavioral factors that relate to the specific components of social disadvantage that are associated with new- born MSC biology. Aim 5 will establish a shared repository (biobank) of MSC, cord blood, cord and placental tissue samples for future studies of molecular mechanisms (gene expression profiles, epigenetic characteristics) and in vitro cell differentiation analyses. Significance and impact: 1) Our study will define novel measures (with norms) in human newborn stem cells that profile the earliest vulnerabilities for health and population health disparities; 2) broaden understanding of novel cellular targets and molecular mechanisms underlying biological embedding of social disad- vantage, that, in turn, may inform risk identification, prevention, early diagnosis, and personalized intervention; and 3) provide a unique and valuable shared resource (human newborn stem cell culture biobank).

抽象的处于社会劣势是人口健康差异的最显着的决定因素。在理解社会劣势如何在生物学上根深蒂固方面取得了重大进展，这一点至关重要生物嵌入主要是在分化的细胞类型和水平上进行描述的。基于以下考虑：a) 社会劣势的长期影响远远超出了人的寿命。分化细胞，其补充仅来自干细胞/祖细胞，并且b）可以在整个细胞中永久存在经过几代人的努力，我们提出了一个新的假设，即健康差异的根源可能会一直延伸到干细胞的影响，特别是母亲社会弱势暴露对后代干细胞的影响我们提出的研究将重点关注西班牙裔、非西班牙裔黑人和非西班牙裔之间的差异。白人母亲及其新生儿的肥胖和代谢表型；间充质祖细胞/基质细胞 (MSC) 和 MSC- 衍生的脂肪细胞作为感兴趣的干细胞和分化细胞；关于线粒体功能、脂肪形成倾向/活性和胰岛素敏感性作为重要的关键细胞内过程；对新生儿脂肪组织质量和葡萄糖胰岛素调节的影响作为重要的结果；以及作为直接传播途径的母胎妊娠生物学。在 N = 240 名儿童-母亲二人组中进行这项研究，从新生儿脐带中分离和培养胎儿 MSC；组织；进行高分辨率细胞实验；并表征 MSC 来源的体外新生儿表型目标 1 将检验母亲暴露于社会的假设。缺点与新生儿间充质干细胞的特性有关，即线粒体效率降低，增加脂肪形成倾向，并降低胰岛素敏感性，目标 2 将检验以下假设：ma- 的变化。内部和胎儿妊娠生物学（内分泌、免疫/炎症和代谢配体的综合测量）介导社会不利条件对新生儿间充质干细胞的影响目标 3 将建立临床研究。 a) 细胞水平 (MSC- 衍生脂肪细胞大小和脂肪含量；脂肪生成活性；b) 全身水平（百分比）目标 4（探索性）将阐明潜在可改变的母亲社会心理以及与新的社会劣势的特定组成部分相关的行为因素目标 5 将建立 MSC、脐带血、脐带和胎盘组织的共享存储库（生物库）。用于未来分子机制（基因表达谱、表观遗传特征）和体外细胞研究的样本差异分析的意义和影响：1）我们的研究将定义人类的新措施（带有规范）。新生儿干细胞可揭示健康和人口健康差异的最早脆弱性 2) 扩大；了解社会缺陷的生物嵌入背后的新细胞靶点和分子机制优势，反过来可以为风险识别、预防、早期诊断和个性化干预提供信息； 3）提供独特且有价值的共享资源（人类新生儿干细胞培养生物库）。