Epigenetic signatures linking maternal adversity and infant neurobiology

连接母亲逆境和婴儿神经生物学的表观遗传特征

• 批准号: 10055332
• 负责人: KARLEN LYONS-RUTH
• 金额: $ 23.48万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055332
• 关键词: Acceleration; Address; Adrenal Glands; Adult; Affect; Age; Age-Months; Aging; Alcoholism; Amygdaloid structure; Behavior; Behavioral; Behavioral Mechanisms; Biological; Biological Aging; Biological Assay; Biological Markers; Boston; Brain; Brain region; Caring; Child; Child Abuse; Child Abuse and Neglect; Child Development; Child Health; Child Rearing; Childhood; Chronic stress; Cognitive; Collaborations; DNA Methylation; Data; Depression and Suicide; Development; Drug abuse; Early Intervention; Epigenetic Process; Exposure to; Funding; Gene Expression; Gene Expression Regulation; Genetic Markers; Genomics; Glucocorticoids; Grant; Health; Health Care Costs; Hippocampus (Brain); Hospitals; Human; Hydrocortisone; Hypothalamic structure; Infant; Infant Development; Influentials; Interruption; Intervention; Lead; Link; Measurable; Measures; Mediating; Medical; Mental Health; Mental disorders; Methods; Mothers; Neonatal; Neurobiology; Paper; Parents; Pediatric Hospitals; Personal Satisfaction; Pituitary Gland; Plant Roots; Play; Population Attributable Risks; Psychopathology; Public Health; Quality of Care; Recording of previous events; Regulation; Research; Research Personnel; Risk; Role; Saliva; Salivary; Sampling; Statistical Data Interpretation; Stress; System; Therapeutic Intervention; Time; Translational Research; Work; biological adaptation to stress; brain volume; caregiving; childhood adversity; design; early detection biomarkers; early experience; early life adversity; epigenetic marker; experience; genome wide methylation; genome-wide; hypothalamic-pituitary-adrenal axis; infancy; intergenerational; maltreatment; maternal caregiving; methylation pattern; neuroimaging; preempt; prevent; specific biomarkers; tool development; transmission process

Abstract Childhood adversity accounts for 50-75% of the population attributable risk for alcoholism, drug abuse, depression, and suicide. Adults’ experiences of maltreatment in childhood often lead to the intergenerational transmission of abusive or neglectful parenting behaviors, dysregulation in their children’s stress response systems, and heightened risk for psychopathology in both parent and child. Emerging research suggests that genome-wide methylation and accelerated epigenetic aging are also associated with prior experiences of child maltreatment. However, no studies have assessed the extent to which epigenetic aging and methylation patterns in human mothers and their infants are involved in conveying the impact of early adversity from mother to child. This proposal seeks funding to support epigenetic assaying of banked maternal and infant saliva samples in collaboration with the epigenetics lab of PI Dr. Kerry Ressler to allow the analysis of the resultant epigenetic data in relation to maternal and infant stress regulation, maternal-infant interaction quality, and development of the infant limbic brain. We will address this agenda by leveraging data our team has collected under R01HD079484 (Multi PI’s Dr. Teicher, McLean Hospital; Dr. Lyons-Ruth, Cambridge Hospital; Drs. Bosquet Enlow and Grant, Boston Children’s Hospital) from 150 mother-infant dyads, weighted for maternal childhood maltreatment and assessed at 4 and 15 months infant age. The first aim of this proposal will evaluate whether maternal childhood maltreatment is linked to acceleration of epigenetic aging and differential genome-wide DNA methylation in both mothers and infants, The second aim will assess whether maternal and infant epigenetic status are linked to atypical maternal and infant cortisol reactivity. The third aim will assess whether caregiving quality is related to maternal epigenetic status and infant epigenetic status. The final aim will assess whether infant epigenetic status is associated with alterations in infant limbic brain regions, particularly the amygdala and hippocampus. This initiative will be led by multiple investigators with specific expertise in: (1) epigenetic programming; (2) neurobiological effects of childhood abuse (3) maternal caregiving quality; and (4) neonatal neuroimaging. Childhood adversity and disrupted parenting are the root preventable causes for a host of medical and psychiatric disorders that result in enormous public health costs. A detailed understanding of underlying mechanisms, critical time points, and mediating factors is necessary to identify early biomarkers for infant risk and to design targeted interventions to preempt the intergenerational consequences of early adversity. We expect that the current proposal will identify specific biomarkers for risk measurable in infancy, which are currently lacking. Such biomarkers will contribute to the development of early interventions to prevent the substantial burden of stress-related health, mental health, cognitive, and addictive problems these infants are at increased risk to experience.

摘要 儿童时期的逆境占人口归因于酗酒，吸毒， 抑郁和自杀成年人在童年时遭受虐待的经历往往导致代际间的暴力行为。 虐待或疏忽的父母行为的传播，孩子的压力反应失调 系统，以及父母和孩子的精神病理学风险增加。新的研究表明， 全基因组甲基化和加速的表观遗传衰老也与儿童的既往经历有关。 虐待然而，还没有研究评估表观遗传老化和甲基化在多大程度上影响了 人类母亲及其婴儿的模式参与传达早期逆境的影响， 从母亲到孩子该提案寻求资金，以支持对库存的孕产妇和婴儿进行表观遗传分析。 唾液样本与PI博士的表观遗传学实验室合作。 由此产生的表观遗传数据与母婴压力调节，母婴互动质量， 和婴儿大脑边缘系统的发育。我们将利用我们团队掌握的数据来解决这一问题 根据R 01 HD 079484收集（Multi PI的Teicher博士，姆克林医院; Lyons-Ruth博士，剑桥医院; Drs. Bosquet Enlow和Grant，波士顿儿童医院）从150个母婴对中，加权为 在4个月和15个月的婴儿年龄进行评估。这项建议的第一个目的是 将评估母亲童年虐待是否与表观遗传衰老的加速有关， 母亲和婴儿的差异全基因组DNA甲基化，第二个目标将评估是否 母亲和婴儿的表观遗传状态与非典型的母亲和婴儿皮质醇反应性有关。第三个目标 将评估分娩质量是否与母体表观遗传状态和婴儿表观遗传状态有关。的 最后一个目的是评估婴儿的表观遗传状态是否与婴儿边缘系统的改变有关 特别是杏仁核和海马体。这项举措将由多名调查人员领导， 在以下方面具有专门知识：（1）表观遗传规划;（2）儿童期虐待的神经生物学影响;（3）孕产妇 新生儿神经影像学检查。童年的不幸和被打乱的养育是根源 这些疾病是许多医疗和精神疾病的可预防原因，导致巨大的公共卫生费用。 对潜在机制、关键时间点和中介因素的详细了解是必要的， 确定婴儿风险的早期生物标志物，并设计有针对性的干预措施，以预防代际风险 早期逆境的后果。我们希望目前的提案将确定风险的特定生物标志物 在婴儿期就可以测量，这是目前所缺乏的。这些生物标志物将有助于早期癌症的发展。 干预措施，以防止与压力有关的健康，心理健康，认知和成瘾的重大负担 这些婴儿经历这些问题的风险增加。