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).

抽象的 我们的目标是检验人类中关于慢性应激和与压力有关的生物行为过程的新假设对 茎/祖细胞生物学。尽管在理解压力如何变得生物学上已经取得了重大进展 嵌入以产生长期效果，仍然存在关键的知识差距。生物嵌入中实施的过程 丁主要在形成组织和器官系统的分化细胞类型的水平上进行了描述。基于 考虑到压力的长期影响可以远远超出最差异的寿命 细胞，其复制品不是从已经分化的“父”细胞中出现的，而是从茎/祖细胞出现的 细胞，我们推进了这样一个假设，即慢性应激作用的生物学嵌入可能一直延伸至茎的水平 细胞，定义其生物学的基本方面，这些方面确定了常见压力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，专门针对造血（HSC）和 间充质干/祖细胞（MSC），以及其端粒和线粒体系统的功能能力作为我们 主要结果。我们使用孕妇同性载荷的复合生物学测量来实现慢性应激 结合了妊娠应力传递途径的主要生物标志物。因为压力响应是关键 慢性应激效应的调节剂，我们还建议通过A中的HSC和MSC表征此表型 体外氧化应激[H2O2]挑战。我们将在n = 300个母子二元组中进行拟议的研究；隔离 培养的新生儿HSC和MSC分别来自脐带血和索组织；并执行细胞 端粒酶活性和高分辨率呼​​吸测定实验，以表征端粒和线粒体功能 容量。 AIM 1将检验以下假设，即慢性应激暴露（同层负荷）可能与功能降低有关 新生儿HSC和MSC端粒和线粒体系统的容量。 AIM 2A将检验慢性应激暴露的假设 素数新生儿HSC和MSC的压力反应性表型，AIM 2B将决定抗氧化剂（白藜芦醇）是否是否 预处理减轻了这种效果。这两个目标都将包括测试对性别修改和端粒和关键协变量的效果。 线粒体功能。 AIM 3将阐明孕产妇社会人口统计学，社会心理，行为和生物物理确定词 使用最先进的机器学习和 预测方法。 AIM 4将建立HSC，MSC，Cord Blood，Cord和Placenal的共享生物库存储库 组织样品，用于未来的分子机制研究（基因表达，表观遗传学特征）和体外不同 - tiation。意义和影响：我们的项目将1）定义人类新生儿的新颖措施（及其规范） 构成细胞健康脆弱性的干细胞和与年龄有关的疾病的风险； 2）扩大不足 新型细胞靶标和压力生物学嵌入的分子机制的存在，这反过来又 可以告知个性化干预措施的发展； 3）提供共享资源（人类新生儿茎 细胞，胎盘，绳索和脐带血生物库）。