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.

已知成人疾病或障碍的风险受到产前/生命早期环境的影响。基础上 Barker及其同事的开创性研究，他们报告了低出生体重与生物学 成人疾病的风险，支持“健康和疾病的发育起源”（DOHaD）假说， 发展到包括低出生体重以外的早期生活逆境，并扩展到代谢以外的结果 综合征特别相关的是，产前酒精暴露（PAE），除了其致畸作用，可以 计划发展神经生物系统，从而增加生命过程中疾病/障碍的风险。 我们的CIFASD发展项目是第一个确定母亲饮酒， 炎症和儿童结局;孕妇独特的免疫特征被确定为与 与他们是否饮酒以及他们孩子的神经发育结果有关。的 拟议的UO 1建立在这些发现的基础上，以检查孕妇和出生后儿童的免疫状况 直到成年我们的工作假设是，产前酒精诱导的免疫/ 炎症系统将与不利的健康、功能和适应性结果相关，提供见解 风险和复原力的潜在因素。具体目的是：1）使用验证队列来确认 免疫参数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）来自匹配的母婴的血浆样品和神经行为结果，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，和一个 来自明尼苏达州的儿童队列（Wozniak）。对来自不同文化/种族、社会经济地位和 环境条件将提供深入了解因素调节酒精的编程效果，并增加 了解免疫变量作为酒精摄入的生物标志物和PAE相关的预测因素 结果。2)通过对亚特兰大队列的评估，将免疫系统的评估扩展到成年期 （科尔斯）、西雅图（格兰特）和不列颠哥伦比亚省（温伯格、卢克、奥伯兰德、卢特克）。我们将调查是否 身体/心理健康和认知和适应性结果受损与免疫/炎症相关 系统失调导致产前编程酒精的影响。对于这两个目标，我们将分析 获得过去和当前的精神/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层面， CIFASD，重点是多哈/健康成果，这是一个至关重要但研究相对不足的领域。此外，委员会认为， 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。