Early Life Stress and Immune Dysfunction in Post-Institutionalized Adolescents

收容后青少年的早期生活压力和免疫功能障碍

基本信息

批准号：
9229564
负责人：
CHRISTOPHER L COE
金额：
$ 19.1万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-19 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9229564
关键词：
17 year old Abnormal Cell Address Adolescence Adolescent Adopted Adoption Adrenal Glands Adult Affect American Animal Model B-Lymphocytes Behavioral Biology Bioperiodicity Blood Circulation Blood specimen Brain C-reactive protein CD28 gene CD3 Antigens CD8-Positive T-Lymphocytes Caring Cells Child Child health care Childhood Circadian Rhythms Color Complete Blood Count Country Cultured Cells Data Development Diagnostic tests Eastern Europe Endotoxins Event Family Feedback Goals Health Hormones Human Hydrocortisone Hypothalamic structure Immune Immune System Diseases Immune System and Related Disorders Immune Targeting Immune response Immune system Immunity Immunocompetence Immunology procedure Immunophenotyping Impaired health In Vitro Individual Infant Infection Inflammatory Institution Institutionalized Adolescent Intervention Learning Life Life Stress Link Literature Longevity Lymphocyte Lymphocyte Subset Measures Mediating Mental Health Mononuclear Neurosecretory Systems Orphanages Parents Pattern Phase Phenotype Pituitary Gland Population Preventive care Principal Investigator Public Health Recording of previous events Recovery Research Resources Risk Russia Saliva Sample Size Severities Shapes Signal Transduction Stress System T cell differentiation T-Lymphocyte Teenagers Testing UNICEF Variant Work Youth abuse neglect adopted child base cytokine deprivation directed attention experience immune function immune health immunoreaction immunoregulation improved infancy innovation neglect preclinical study prenatal prevent programs public health relevance resilience response trafficking

项目摘要

DESCRIPTION (provided by applicant): There is a dearth of evidence in humans definitively showing that stress confined to the prenatal-infancy period has programming-like effects on the immune system. In addition, human studies of immune correlates of adverse childhood conditions have not focused specifically T-cell phenotypes involved in immune regulation that may compromise the ability to respond to infection. Both of these gaps in the literature are highly significant in that they limit our ability to understand the mechanisms through which early life stress (ELS) impairs health across the life span. This R21 addresses these lacunae by conducting sophisticated immunophenotyping and functional immune assays in a unique population of youth (14 through 17 years of age) who as infants (< 36 months) were adopted from orphanages/institutions in Russia/Eastern Europe into well-resourced and generally stable, low-life-stress families in the US. The early life stress (ELS) for these youth, thus, was confined to the prenatal-infancy period. There are two aims. Aim 1: Determine the impact of ELS on immune responses of these youth now that they are adolescents. Blood samples will be obtained from 30 post-institutionalized (PI) and 30 comparison adolescents. Sophisticated multi-color immunophenotyping will be used to characterize lymphocyte subsets and mononuclear cell responses will be probed in vitro with stimulants, and cytokine levels in supernatants determined with multi-cytokine arrays. Complete blood counts and C-reactive protein levels also will be determined. Saliva cortisol collected at testing will assess whether transient cortisol elevations in response to blood sampling contribute to the immune differences between groups. Aim 2. Delineate factors that account for differential vulnerability among ELS youth, including distorted hormone biorhythms and severity of the ELS. The second phase of this project will expand the sample size to include 30 additional PI's (total=60), providing sufficient diversity to determine the influence of the severity and duration of institutional care and the mediating influence of dysregulated HPA diurnal rhythms to predict variation in the T cell repertoire and cellular responses in stimulated cultures. This work is highly significant because, by focusing on youth who experience radical improvements in care post-infancy, it will provide the strongest evidence to date of prenatal-infancy programming-like effects on the human immune system and underscores the importance of preventing early deprivation and neglect. It also has potential significance for improving the preventive care of individuals with a history of early adverse care, by delineating specific immune alterations that may underlie potential health risks later in adulthood. It is highly innovative in being the first study of ELS in humans to employ such a sophisticated immune panel and to combine measures that are integral to a pro-inflammatory bias and immune competence. This R21 project will lay the groundwork for a new avenue of ELS-immune research that is focused on lingering sequelae of childhood experiences.

描述（由适用提供）：人类中有证据的死亡，明确表明，局限于产前期限时期的压力对免疫系统具有类似编程的影响。此外，人类对不良儿童条件的免疫复合物的研究并未集中在可能损害对感染能力的免疫调节中涉及的T细胞表型。文献中的这两个差距都非常重要，因为它们限制了我们了解早期生活压力（ELS）损害整个生命周期的机制的能力。该R21通过在独特的年轻人（14至17岁）中进行复杂的免疫表型和功能性免疫驴来解决这些空白，这些驴子作为婴儿（<36个月）被俄罗斯/东欧的孤儿院（<36个月）所采用，分为我们美国的孤儿院/机构，通常是在美国美国使用的孤儿院/机构。这些年轻人的早期生活压力（EL）被限制到产前期间。有两个目标。目标1：确定EL对这些年轻人的免疫反应的影响，因为他们是青少年。血样将从30个机构化后（PI）和30个比较青少年中获得。复杂的多色免疫肾上腺素型将用于表征淋巴细胞亚群，并用刺激剂在体外探测单核细胞的反应，并用多环阵阵列确定的上清液中的细胞因子水平。还将确定完整的血液计数和C反应蛋白水平。测试时收集的唾液皮质醇将评估瞬时皮质醇升高是否响应血液采样响应，导致组之间的免疫差异。目标2。描述了ELS青年的差异脆弱性的描述因素，包括扭曲的Horsene生物节律和EL的严重程度。该项目的第二阶段将扩大样本量，包括30个额外的PI（总计= 60），提供了足够的多样性，以确定机构护理的严重程度和持续时间的影响以及HPA昼夜节律失调的中介影响，以预测T细胞曲目和细胞反应在受刺激培养物中的变化。这项工作非常重要，因为，通过关注年轻人在赛后的彻底改善的年轻人，它将提供有力的证据，以迄今为止对人类免疫系统的类似于人类免疫系统的影响，并强调了防止早期剥夺和忽视的重要性。通过描述特定的免疫学改变可能是成年后期潜在的健康风险的基础，它还可以改善具有早期不良护理病史的个体的预防性护理的潜在意义。作为人类EL的首次研究是采用如此复杂的免疫学面板并结合促炎性偏见和免疫能力不可或缺的措施的首次研究，这是高度创新的。这个R21项目将为Els-rmmune研究的新途径奠定基础，该研究的重点是挥之不去的童年经历后遗症。