Maternal chronic stress and fetal programming of hematopoietic stem/ progenitor cells

母亲慢性应激和胎儿造血干/祖细胞编程

• 批准号: 529793191
• 负责人: Professorin Dr. Sonja Entringer
• 金额: --
• 依托单位: Institut für Medizinische Psychologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/529793191?language=en
• 关键词: Maternal; chronic; stress; fetal; programming

The goal of the project is to test a novel hypothesis about the impact of maternal chronic stress on her offspring’s stem cells. 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 cells, but only from stem/progenitor cells, we propose that biological embedding of the effects of maternal chronic stress may extend all the way down to characteristics of her offspring’s stem cell biology. We will conduct a study in N=180 mother-child dyads recruited during late gestation and followed through birth. We operationalize maternal chronic stress using a composite biological measure of maternal allostatic load that incorporates the principal biomarkers of the gestational stress transmission pathway. At birth, we will isolate and culture newborn hematopoietic stem and progenitor cells (HSCs) from umbilical cord blood. HSCs give rise to immune cells that are of particular relevance in the context of immune system- and age-related disorders. We will characterize cellular processes that play a central role in maintenance of DNA integrity, i.e., telomerase functional capacity and DNA repair capacity. Because stress responsivity is a key modulator of chronic stress effects, we additionally propose to characterize this phenotype in HSCs via an in vitro biological stress challenge (pre-incubation with cortisol or IL-6). To establish the relevance of variation in newborn HSC telomere biology for immune function, we will characterize the immune/inflammatory response of neonatal (cord) blood immune cells to antigen challenge. Aim 1 will test the hypothesis that maternal chronic stress exposure is prospectively associated with reduced telomerase functional capacity and DNA repair capacity of fetal (newborn) HSCs. Aim 2A will test the hypothesis that maternal chronic stress exposure is associated with the stress responsivity phenotype (response to cortisol or IL-6 challenge) of fetal HSC cellular function. Aim 2B will test the hypothesis that antioxidant (resveratrol) pre-treatment attenuates the expected effects in Aim 2A. Aim 3 will test the strength of the associations between fetal HSC telomerase functional capacity and DNA repair capacity and newborn immune function. Our study will define novel measures in human newborn stem cells that profile the earliest vulnerabilities for cellular health, aging and risk of age-related disorders. Our findings will broaden understanding of novel cellular targets and molecular mechanisms underlying biological embedding of stress, that, in turn, may inform risk identification, prevention, early diagnosis, and personalized intervention.

该项目的目标是测试一种新的假说，即母亲的慢性压力对其后代干细胞的影响。考虑到应激的长期影响可能远远超出大多数分化细胞的寿命，这些细胞的补充不是来自已经分化的细胞，而是仅仅来自干细胞/祖细胞，我们提出，母亲慢性应激的影响的生物嵌入可能一直延伸到她的后代的干细胞生物学特征。我们将在妊娠晚期招募的N=180个母子二人组中进行一项研究，并跟踪调查整个分娩过程。我们使用一种母体等静负荷的复合生物学测量方法来操作母体慢性应激，该方法结合了妊娠应激传递途径的主要生物标记物。出生时，我们将从脐带血中分离和培养新生儿造血干/祖细胞(HSCs)。造血干细胞产生的免疫细胞在免疫系统和年龄相关疾病的背景下具有特别重要的意义。我们将描述在维持DNA完整性中起核心作用的细胞过程，即端粒酶功能能力和DNA修复能力。由于应激反应是慢性应激效应的关键调节因子，我们还建议通过体外生物应激挑战(预先与皮质醇或IL-6孵育)来表征HSCs的这一表型。为了确定新生儿HSC端粒生物学变异与免疫功能的相关性，我们将表征新生儿(脐带血)免疫细胞对抗原攻击的免疫/炎症反应。目的1验证母体慢性应激暴露与胎儿(新生儿)HSCs端粒酶功能和DNA修复能力降低相关的假设。目的验证母体慢性应激暴露与胎儿HSC细胞功能的应激反应表型(对皮质醇或IL-6刺激的反应)相关的假设。目标2B将检验抗氧化剂(白藜芦醇)预治疗减弱目标2A预期效果的假设。目的3将测试胎儿HSC端粒酶功能能力与DNA修复能力和新生儿免疫功能之间的相关性。我们的研究将在人类新生儿干细胞中定义新的测量方法，描述细胞健康、衰老和与年龄相关的疾病风险的最早脆弱性。我们的发现将扩大对新的细胞靶点和生物嵌入应激的分子机制的理解，这反过来可能为风险识别、预防、早期诊断和个性化干预提供信息。