Stress and Human Stem/Progenitor Cells: Biobehavioral Mechanisms

压力与人类干/祖细胞：生物行为机制

• 批准号: 10522469
• 负责人: Kristen Elizabeth Boyle
• 金额: $ 70.79万
• 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: 2022-08-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522469
• 关键词: Activities of Daily Living; Address; Age; Aging; Animals; Antioxidants; Attenuated; Basic Science; Behavioral; Bioenergetics; Biological; Biological Markers; Biological Phenomena; Biology; Biophysics; Birth; Body mass index; Cell Culture System; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell physiology; Cells; Cellular biology; Characteristics; Child; Chronic stress; Clinical Investigator; Coupled; Data; Development; Diet; Disease; Embryo; Endocrine; Ensure; Epigenetic Process; Ethnic Origin; Exposure to; Follow-Up Studies; Functional disorder; Future; Gene Expression; Generations; Genetic; Goals; Gold; Growth; Health; Hematopoietic; Hematopoietic stem cells; Human; Hydrogen Peroxide; Immune; In Vitro; Individual Differences; Inflammatory; Intervention; Knowledge; Life; Long-Term Effects; Longevity; Measures; Mesenchymal; Mesenchymal Stem Cells; Metabolic; Methods; Mitochondria; Modification; Molecular; Mothers; Newborn Infant; Oxidative Stress; Parents; Pathway interactions; Personal Satisfaction; Phenotype; Physical activity; Physiological; Physiology; Placenta; Population; Population Heterogeneity; Predisposition; Pregnancy; Process; Psychosocial Stress; Publishing; Race; Reactive Oxygen Species; Research Design; Research Personnel; Resolution; Resource Sharing; Resveratrol; Risk; Skin; Sleep; Social support; Standardization; Stress; Stromal Cells; System; Systems Biology; Telomerase; Testing; Time; Tissue Sample; Tissues; Umbilical Cord Blood; Variant; adult stem cell; adverse birth outcomes; age related; allostatic load; base; biobank; biobehavior; body system; cell type; cellular targeting; classification trees; experimental study; fetal; genome integrity; gestational weight gain; human stem cells; imprint; in vivo; innovation; intrapartum; machine learning prediction; maternal stress; novel; offspring; personalized intervention; personalized predictions; predictive modeling; prepregnancy; primary outcome; prognostic; prospective; psychosocial; recruit; regression trees; repository; resilience; response; senescence; sex; sociodemographics; stem; stem cell biology; stem cells; telomere; translational approach; transmission process

ABSTRACT Our goal is to test a novel hypothesis in humans about the impact of chronic stress and stress-related biobehavioral processes on stem/progenitor cell biology. Although substantial progress has been made in understanding how stress becomes biologically embedded to produce long-term effects, crucial knowledge gaps remain. The processes implicated in biological embed- ding have been described primarily at the level of differentiated cells types that form tissues and organ systems. Based on the consideration that the long-term effects of stress can extend well beyond the lifespan of most differentiated cells, whose replenishment does not occur from already-differentiated ‘parent’ cells, but occurs from stem/progenitor cells, we advance the hypothesis that biological embedding of the effects of chronic stress may extend all the way down to the level of stem cells, to define fundamental aspects of their biology that determine the earliest vulnerabilities for common stress- and age-related disorders. We underscore the importance of studying fetal (newborn) stem cells, focus specifically on hematopoietic (HSCs) and mesenchymal stem/progenitor cells (MSCs), and on the functional capacity of their telomere and mitochondrial systems as our primary outcomes. We operationalize chronic stress using a composite biological measure of maternal allostatic load that incorporates the principal biomarkers of the gestational stress transmission pathway. Because stress responsivity is a key modulator of chronic stress effects, we additionally propose to characterize this phenotype in HSCs and MSCs via an in vitro oxidative stress [H2O2] challenge. We will conduct the proposed study in N=300 mother-child dyads; isolate and culture newborn HSCs and MSCs from umbilical cord blood and cord tissue, respectively; and perform cellular telomerase activity and high-resolution respirometry experiments to characterize telomere and mitochondrial functional capacity. Aim 1 will test the hypothesis that chronic stress exposure (allostatic load) is prospectively associated with reduced functional capacity of newborn HSC and MSC telomere and mitochondrial systems. Aim 2A will test the hypothesis that chronic stress exposure primes the stress responsivity phenotype of newborn HSCs and MSCs, and Aim 2B will determine whether antioxidant (resveratrol) pretreatment attenuates this effect. Both aims will include tests for effect modification by sex and key covariates of telomere and mitochondrial function. Aim 3 will elucidate the maternal sociodemographic, psychosocial, behavioral and biophysical determinants of variation in components of allostatic load that impact newborn HSC/MSC biology using state-of-the-art machine learning and prediction approaches. Aim 4 will establish a shared Biobank repository of HSC, MSC, cord blood, cord and placental tissue samples for future studies of molecular mechanisms (gene expression, epigenetic profiles) and in vitro differen- tiation. Significance and Impact: Our project will 1) define novel measures (and their norms) in human newborn stem cells that profile the earliest vulnerabilities for cell health and risk of age-related disorders; 2) broaden under- standing of novel cellular targets and molecular mechanisms underlying biological embedding of stress, that, in turn, may inform the development of personalized interventions; and 3) provide shared resources (human newborn stem cell, placenta, cord, and cord blood biobank).

摘要 我们的目标是在人类身上测试一种新的假说，即慢性压力和与压力相关的生物行为过程对 干细胞/祖细胞生物学。尽管在理解压力是如何从生物学上形成的方面取得了实质性进展 为了产生长期效果，关键的知识差距依然存在。生物嵌入中所涉及的过程- Ding主要是在形成组织和器官系统的分化细胞类型的水平上被描述的。基座 考虑到压力的长期影响可能远远超出最分化的人的寿命 细胞，其补充不是来自已经分化的‘亲代’细胞，而是来自干细胞/祖细胞 细胞，我们提出了一个假设，即慢性应激效应的生物嵌入可能一直延伸到干细胞水平。 细胞，以确定其生物学的基本方面，确定常见的应激和年龄相关疾病的最早脆弱性。 我们强调研究胎儿(新生儿)干细胞的重要性，特别关注造血(HSCs)和 间充质干细胞(MSCs)及其端粒和线粒体系统的功能能力 主要结果。我们使用母体不平衡负荷的复合生物学测量来操作慢性应激 结合了妊娠应激传递途径的主要生物标志物。因为压力响应性是一个关键 作为慢性应激效应的调节者，我们还建议通过一种 体外氧化应激[过氧化氢]挑战。我们将在N=300个母子二元组中进行拟议的研究；分离 分别从脐带血和脐带组织中培养新生儿HSCs和MSCs； 端粒酶活性和高分辨率呼吸测量实验表征端粒和线粒体功能 容量。目标1将检验以下假设：慢性应激暴露(静力负荷)可能与功能减退有关 新生儿HSC和MSC端粒和线粒体系统的能力。Aim 2A将测试慢性应激暴露的假设 启动新生儿造血干细胞和骨髓间充质干细胞的应激反应表型，目标2B将决定抗氧化剂(白藜芦醇) 预处理会减弱这种影响。这两个目标都将包括通过性别和端粒和端粒的关键辅助变量进行效果修改的测试 线粒体功能。目标3将阐明母亲的社会人口学、心理社会、行为和生物物理决定因素 使用最先进的机器学习和研究影响新生儿HSC/MSC生物学的恒定负荷成分的变化 预测方法。目标4将建立HSC、MSC、脐带血、脐带血和胎盘的共享生物库 用于进一步研究分子机制(基因表达、表观遗传学特征)的组织样本和体外差异。 时间到了。意义和影响：我们的项目将1)定义新的人类新生儿测量方法(及其标准) 描述细胞健康和年龄相关疾病风险的最早脆弱性的干细胞；2)扩大- 新的细胞靶点和压力生物嵌入的分子机制的地位，这反过来， 可为个性化干预措施的发展提供信息；以及3)提供共享资源(人类新生儿干细胞 细胞、胎盘、脐带和脐带血生物库)。