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

• 批准号: 10710216
• 负责人: Kristen Elizabeth Boyle
• 金额: $ 62.27万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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/10710216
• 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; Disparity; Early Diagnosis; Embryo; Endocrine; Ensure; Epigenetic Process; Ethnic Origin; Exposure to; Fatty acid glycerol esters; Functional disorder; Future; Gene Expression; Generations; 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; PPAR gamma; Participant; Pathway interactions; 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; beta catenin; 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; progenitor; psychosocial; recruit; sex; shared repository; social disparities; stem; stem cell biology; stem cell function; stem cell population; stem cells; translational approach; transmission process

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).

摘要 处于社会不利地位是人口健康差距的最突出决定因素。虽然分- 在理解社会劣势如何成为生物学上根深蒂固的、至关重要的 知识差距依然存在。生物包埋主要在分化细胞类型的水平上进行了描述， 组织中基于以下考虑：（a）社会不利地位的长期影响远远超出了人的寿命， 分化的细胞，其补充仅从干/祖细胞发生，和B）可以跨 几代人，我们提出了一个新的假设，即健康差距的起源可能会一直延伸到水平 干细胞，特别是对后代干细胞的母亲的社会不利暴露的影响， 胚胎/胎儿生命。我们建议的研究将集中在西班牙裔，非西班牙裔黑人和非西班牙裔之间的差异 肥胖和代谢表型中的白色母亲及其新生儿;间充质祖细胞/基质细胞（MSC）和MSC-1 衍生的脂肪细胞作为感兴趣的干细胞和分化细胞;对线粒体功能、成脂倾向/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 作为重要的结果;以及母胎妊娠生物学作为最近的传播途径。我们将 在N = 240个儿童-母亲配对的队列中进行这项研究;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;并在体外表征MSC衍生的新生儿表型 adipocyte和体内使用全身密度测定法。目的1将检验母亲暴露于社会环境的假设， 缺点与新生间充质干细胞的特性有关，即，线粒体效率降低， 增加的脂肪形成倾向和降低的胰岛素敏感性。目标2将测试的假设，在马的变化- 母体和胎儿妊娠生物学（内分泌、免疫/炎症和代谢配体的综合指标） 介导社会不利对新生间充质干细胞的影响。目标3将建立临床 新生儿肥胖相关表型的MSC特征变化的意义a）细胞水平（MSC- 衍生的脂肪细胞大小和脂肪含量;线粒体功能;脂肪形成活性），和B）全身水平（百分比 脂肪量和全身胰岛素敏感性）。目的4（探索性）将阐明潜在的可改变的孕产妇心理社会 和行为因素，涉及社会不利的具体组成部分，与新的- 生物学硕士目的5建立MSC、脐带血、脐带和胎盘组织的共享库（生物库） 用于分子机制（基因表达谱、表观遗传特征）和体外细胞 差异化分析意义和影响：1）我们的研究将定义新的措施（与规范）在人类 新生儿干细胞，描绘健康和人口健康差距的最早脆弱性; 2）扩大 了解新的细胞靶点和社会疾病生物学嵌入的分子机制， 优势，这反过来又可以为风险识别、预防、早期诊断和个性化干预提供信息; 3)提供一个独特而宝贵的共享资源（人类新生儿干细胞培养生物库）。