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: 10254338
• 负责人: KARLEN LYONS-RUTH
• 金额: $ 25.12万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254338
• 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; 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; saliva sample; 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.

抽象的 50-75%的人口在童年时期遭遇逆境，导致酗酒、吸毒、 抑郁症和自杀。成年人在童年时期遭受虐待的经历往往会导致代际间的 虐待或疏忽的养育行为的传播，孩子的压力反应失调 系统，以及父母和孩子患精神病理学的风险增加。新兴研究表明 全基因组甲基化和加速表观遗传衰老也与儿童的先前经历有关 虐待。然而，没有研究评估表观遗传衰老和甲基化的程度 人类母亲及其婴儿的模式参与传达早期逆境的影响 母亲对孩子。该提案寻求资金支持储存母婴的表观遗传检测 与 PI 博士 Kerry Ressler 的表观遗传学实验室合作，对唾液样本进行分析 由此产生的与母婴压力调节、母婴互动质量相关的表观遗传数据， 和婴儿边缘脑的发育。我们将利用我们团队拥有的数据来解决这一议程 收集于 R01HD079484（Multi PI 的 Teicher 博士，麦克莱恩医院；Lyons-Ruth 博士，剑桥医院； 博士。 Bosquet Enlow 和 Grant，波士顿儿童医院）对 150 名母婴二人进行了加权 母亲儿童期虐待情况并在 4 个月和 15 个月婴儿时进行评估。本提案的第一个目标 将评估母亲儿童期虐待是否与表观遗传衰老加速有关 母亲和婴儿的全基因组 DNA 甲基化差异，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母亲和婴儿皮质醇反应性有关。第三个目标 将评估护理质量是否与母亲表观遗传状态和婴儿表观遗传状态相关。这 最终目标将评估婴儿表观遗传状态是否与婴儿边缘脑的改变相关 区域，特别是杏仁核和海马体。该倡议将由多名研究人员领导 具体专业知识包括：(1) 表观遗传编程； (2) 儿童期虐待对神经生物学的影响 (3) 母亲 护理质量； (4)新生儿神经影像学。童年的逆境和养育方式的破坏是根源 许多医学和精神疾病的可预防原因，导致巨大的公共卫生成本。 详细了解潜在机制、关键时间点和中介因素对于 识别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。我们预计当前的提案将确定特定的风险生物标志物 在婴儿期即可测量，目前尚缺乏。此类生物标志物将有助于早期疾病的发展 预防与压力相关的健康、心理健康、认知和成瘾的重大负担的干预措施 这些婴儿遇到问题的风险更大。