Immune Dysregulation in FASD: Programming of health and neurobehavioral outcomes

FASD 中的免疫失调：健康和神经行为结果的规划

• 批准号: 9390574
• 负责人: JOANNE WEINBERG
• 金额: $ 16.54万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-20 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9390574
• 关键词: Activities of Daily Living; Address; Adjuvant Arthritis; Adult; Alcohol consumption; Alcohol-Related Neurodevelopmental Disorder; Alcohols; Animal Model; Area; Autistic Disorder; Biological; Biological Markers; Birth; Blood specimen; Brain; British Columbia; Child; Childhood; Choline; Clinic; Cognitive; Collaborations; Competence; Data; Development; Dimensions; Disease; Environment; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; Gene Expression; Grant; Health; Immune; Immune response; Immune system; Impaired cognition; Impairment; Individual; Infant; Inflammation; Inflammatory; Informal Social Control; Life; Life Cycle Stages; Link; Low Birth Weight Infant; Measures; Mental Health; Metabolic; Metabolic Diseases; Metabolic syndrome; Minnesota; Modeling; Mothers; Neurobiology; Neurocognition; Neurodevelopmental Disorder; Organism; Outcome; Pediatric Hospitals; Physiological; Plasma; Play; Predictive Factor; Pregnant Women; Psyche structure; Recruitment Activity; Reporting; Research; Research Subjects; Risk; Role; Sampling; Schizophrenia; Seminal; Stress; Suggestion; System; Teratogenic effects; Ukraine; Validation; Work; alcohol effect; alcohol exposure; cohort; cytokine; disorder risk; experience; fetal programming; functional outcomes; immune function; inflammatory marker; insight; neurobehavioral; novel; offspring; physical conditioning; prenatal; prenatal influence; programs; resilience; response

Risk for adult diseases or disorders is known to be influenced by the prenatal/early life environment. Building on seminal studies by Barker and colleagues, who reported associations between low birth weight and biological risk for adult disease, support for the “developmental origins of health and disease” (DOHaD) hypothesis has grown to include early life adversities beyond low birth weight and to extend to outcomes beyond metabolic syndrome. Of particular relevance, prenatal alcohol exposure (PAE), in addition to its teratogenic effects, can program developing neurobiological systems and thus increase risk for diseases/ disorders over the life course. Our CIFASD Developmental Project is the first to identify links among maternal alcohol consumption, inflammation, and child outcomes; unique immune signatures in pregnant women were identified in association with whether or not they consumed alcohol and with neurodevelopmental outcomes of their children. The proposed UO1 builds on these findings to examine immune profiles in pregnant women and children from birth through adulthood. Our working hypothesis is that prenatal alcohol-induced dysregulation of immune/ inflammatory systems will be associated with adverse health, functional and adaptive outcomes, providing insight into factors underlying risk and resilience. Specific Aims are to: 1) Use validation cohorts to confirm the utility of immune parameters as possible biomarkers and predictors of alcohol-related health and neurobehavioral outcomes, by analyzing: a) plasma samples and neurobehavioral outcomes from matched mother-infant or mother-child pairs from Ukraine (Chambers) and San Diego (Chambers, Jones, Mattson), respectively, and a child cohort from Minnesota (Wozniak). Assessment of individuals from different cultural/ethnic, SES, and environmental conditions will provide insight into factors modulating alcohol’s programming effects, and increase understanding of immune variables as biomarkers of alcohol intake and predictive factors for PAE-related outcomes. 2) Extend assessment of the immune system into adulthood with assessment of cohorts from Atlanta (Coles), Seattle (Grant), and British Columbia (Weinberg, Loock, Oberlander, Lutke). We will investigate whether physical/mental health and impaired cognitive and adaptive outcomes are associated with immune/inflammatory system dysregulation resulting from prenatal programming effects of alcohol. For both Aims, we will analyze cytokines/inflammatory markers in plasma, obtain past and current mental/physical health information, and measure neurobehavioral and adaptive outcomes, providing novel insight into links among immune function, cognitive and adaptive function, and health outcomes. Together, these studies bring a new dimension to CIFASD, a focus on DOHAD/health outcomes, a critically important but relatively understudied area. Moreover, as the immune system plays a key role in brain development, this work has broad implications for understanding the role of immune/inflammatory mechanisms in FASD-associated neurobehavioral and adaptive deficits.

已知成人疾病或紊乱的风险受产前/早期生活环境的影响。在基础上建设 Barker和他的同事进行了开创性的研究，他们报告了低出生体重与生物学之间的联系 成人疾病的风险，支持“健康和疾病的发育起源”(DOHAD)假说 成长到包括低出生体重以外的早期生活逆境，并延伸到新陈代谢以外的结果 综合症。尤其重要的是，产前酒精暴露(PAE)，除了它的致畸作用外，还可能 发展神经生物学系统的计划，从而增加生命过程中疾病/紊乱的风险。 我们的CIFASD发展项目是第一个确定母亲饮酒之间的联系的项目， 炎症与儿童结局；孕妇独特的免疫特征被确定为相关 他们是否饮酒，以及他们孩子的神经发育结果。这个 建议的UO1建立在这些发现的基础上，以检查孕妇和儿童从出生起的免疫状况 一直到成年。我们的工作假设是胎儿期酒精引起的免疫失调。 炎症系统将与不良的健康、功能和适应性结果相关，提供洞察力 转化为潜在的风险和韧性因素。具体目标是：1)使用验证队列来确认 免疫参数可作为酒精相关健康和神经行为的可能生物标志物和预测因子 结果，通过分析：a)配对母婴或 分别来自乌克兰(钱伯斯)和圣地亚哥(钱伯斯、琼斯、马特森)的母子对，以及 来自明尼苏达州(沃兹尼亚克)的儿童队列。对来自不同文化/种族、社会经济地位和 环境条件将提供对酒精编程影响的调节因素的洞察，并增加 免疫变量作为酒精摄入量的生物标志物和PAE相关预测因素的认识 结果。2)通过对来自亚特兰大的队列进行评估，将免疫系统的评估扩展到成年 (Coles)、西雅图(Grant)和不列颠哥伦比亚(Weinberg、Loock、Oberlander、Lutke)。我们将调查是否 身体/心理健康以及认知和适应能力受损与免疫/炎症有关 由酒精的产前编程效应引起的系统失调。对于这两个目标，我们将分析 血浆中的细胞因子/炎症标志物，获得过去和现在的心理/身体健康信息，以及 测量神经行为和适应性结果，为免疫功能之间的联系提供新的见解， 认知和适应功能，以及健康结果。总之，这些研究带来了一个新的维度 CIFASD，重点关注DOHaD/健康结果，这是一个极其重要但相对研究较少的领域。此外， 由于免疫系统在大脑发育中起着关键作用，这项工作对理解 免疫/炎症机制在FASD相关神经行为和适应性缺陷中的作用。