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: 10684115
• 负责人: Kristen Elizabeth Boyle
• 金额: $ 65.07万
• 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/10684115
• 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; 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 Predisposition to Disease; Goals; Growth; Health; Hematopoietic stem cells; Human; Hydrogen Peroxide; Immune; In Vitro; Individual Differences; Inflammatory; Intervention; Knowledge; Life; Long-Term Effects; Longevity; Machine Learning; 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; Publishing; Race; Reactive Oxygen Species; Research Design; Research Personnel; Resolution; Resource Sharing; Resveratrol; Risk; Skin; Sleep; Social support; Spirometry; 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; 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; maternal stress; novel; offspring; personalized intervention; personalized predictions; predictive modeling; prepregnancy; primary outcome; prognostic; prospective; psychosocial; recruit; regression trees; repository; resilience; response; senescence; sex; shared repository; 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 我们的目标是在人类身上测试一项关于慢性压力和压力相关生物行为过程对健康的影响的新假设。 尽管在理解压力如何产生生物学方面已经取得了实质性进展。 嵌入以产生长期影响，但与生物嵌入相关的过程仍然存在关键的知识差距。 ding 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。 考虑到压力的长期影响可能会远远超出大多数差异化人群的寿命 细胞，其补充不是来自已经分化的“亲代”细胞，而是来自干/祖细胞 细胞中，我们提出了这样的假设：慢性应激影响的生物嵌入可能会一直延伸到干细胞水平 细胞，以确定其生物学的基本方面，从而确定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，特别关注造血 (HSC) 和 间充质干细胞/祖细胞 (MSC) 及其端粒和线粒体系统的功能能力 我们使用孕产妇稳态负荷的综合生物学测量来操作慢性压力， 包含妊娠应激传递途径的主要生物标志物，因为应激反应性是关键。 作为慢性应激效应的调节剂，我们还建议通过一种方法来表征 HSC 和 MSC 中的这种表型 我们将在 N=300 例母子分离株中进行体外氧化应激 [H2O2] 挑战。 分别从脐带血和脐带组织中培养新生 HSC 和 MSC，并进行细胞分析； 端粒酶活性和高分辨率呼​​吸测量实验来表征端粒和线粒体功能 目标 1 将检验以下假设：慢性压力暴露（稳态负荷）与功能下降有前瞻性相关。 新生 HSC 和 MSC 端粒和线粒体系统的能力目标 2A 将检验慢性应激暴露的假设。 启动新生 HSC 和 MSC 的应激反应表型，Aim 2B 将确定是否抗氧化剂（白藜芦醇） 预处理会减弱这种影响，这两个目标都包括测试性别和端粒关键协变量的影响。 目标 3 将阐明母亲的社会人口、社会心理、行为和生物物理决定因素。 使用最先进的机器学习和方法来研究影响新生儿 HSC/MSC 生物学的稳态负荷成分的变化 目标 4 将建立 HSC、MSC、脐带血、脐带和胎盘的共享生物库存储库。 用于未来分子机制（基因表达、表观遗传特征）和体外差异研究的组织样本 意义和影响：我们的项目将 1）定义人类新生儿的新措施（及其规范）。 干细胞能够揭示细胞健康的最早脆弱性和年龄相关疾病的风险；2）扩大研究范围； 压力生物嵌入的新细胞靶点和分子机制的地位，反过来， 可以为个性化干预措施的制定提供信息；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）。