Childhood Maltreatment:Biomarkers of Risk and Resilience

童年虐待:风险和复原力的生物标志物

• 批准号: 8506196
• 负责人: AUDREY TYRKA
• 金额: $ 11.66万
• 依托单位: BUTLER HOSPITAL (PROVIDENCE, RI)
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8506196
• 关键词: Adrenal Glands; Adult; Affect; Affective; Alleles; Animal Model; Animals; Anxiety; Attenuated; Behavior; Behavioral; Biological Markers; Brain; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Catechols; Child; Child Abuse and Neglect; Childhood; Clinical Research; Control Groups; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Development; Diagnosis; Disease; Evolution; Functional disorder; Future; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genetic Variation; Glucocorticoid Receptor; Goals; Haplotypes; Hydrocortisone; Hyperactive behavior; Hypothalamic Hormones; Hypothalamic structure; Infant; Life Stress; Major Depressive Disorder; Measures; Mediating; Methyltransferase; Nerve Growth Factors; Neural Pathways; Neurobiology; Neurosecretory Systems; Nursery Schools; Outcome; Peptidyl-Dipeptidase A; Pituitary Gland; Play; Prevention; Primary Prevention; Problem behavior; Promoter Regions; Psychiatric Diagnosis; Psychopathology; Public Health; Receptor Gene; Recording of previous events; Regulation; Research; Risk; Role; Social support; Stress; Structure; System; Time; Transferase; abuse neglect; adverse outcome; aged; base; caregiving; follow-up; gene environment interaction; high risk; hypothalamic-pituitary-adrenal axis; indexing; insertion/deletion mutation; insight; maltreated children; maltreatment; meetings; monoamine; neurotransmission; preclinical study; prospective; public health relevance; resilience; response; serotonin transporter; social; trait

DESCRIPTION (provided by applicant): Childhood maltreatment, in the form of abuse and neglect, is a major public health problem. Maltreated children have elevated rates of internalizing psychopathology and are at high risk for a broad range of adverse outcomes. Infants and young children are at the greatest risk of maltreatment and may have the most severe squeal of maltreatment. Insofar as primary prevention of maltreatment is often not feasible, the identification of factors that influence positive outcomes in maltreated children is critically important. Genetic risk and protective factors appear to play an important role in the behavioral squeal of childhood maltreatment. A number of recent studies have identified specific genes that interact with childhood adversity to produce risk for major depression and anxiety-related traits in adults and children. These include genes that regulate monoamine neurotransmission and neuroendocrine function. One likely mechanism of gene-environment interactions is that risk genes may confer sensitivity to stress, possibly through altered functioning of the HPA axis. A substantial body of evidence documents dysregulation of HPA axis function in animal models of early adversity. A growing body of research in children and adults with a history of early maltreatment provides evidence of dysfunction of this stress system (which may be reflected in exaggerated or attenuated cortisol responses). Converging lines of evidence from preclinical and clinical studies indicate that excessive activation of the HPA axis may be toxic and result in alterations of brain structure and function in circuitry involved in major depression and other disorders. In addition to enduring neuroendocrine effects of early-life stress, such HPA axis hyperactivity may in part result from gene variants involved in the regulation of this stress axis. The goal of the present application is to identify genetic and neuroendocrine predictors of behavior problems and psychopathology in maltreated preschoolers. Genes that regulate monoamine or HPA axis function will be examined based on involvement in neural pathways implicated in these behavioral problems as well as prior empirical associations with internalizing disorders and maltreatment. Further, we seek to determine whether alterations in HPA axis function mediate these relationships. A follow-up assessment will examine prospective relationships between these biomarkers and behavioral outcomes as well as the stability of associations of neuroendocrine activity with behavior. These results should provide valuable information regarding the development of affective and behavioral problems in maltreated children that could guide treatment and prevention efforts as well as direction for future clinical research efforts. PUBLIC HEALTH RELEVANCE: The proposed study seeks to elucidate neurobiological and social risk and protective factors for behavior problems in maltreated children. Results of this study may provide insight into the neurobiological markers and mechanisms of psychopathology in these vulnerable children. Such information may contribute to future treatment and prevention efforts.

描述（由申请人提供）：以虐待和忽视的形式，儿童虐待是一个主要的公共卫生问题。受虐待的儿童内部化精神病理学的率升高，并且有多种不良后果的风险很高。婴儿和幼儿遭受虐待的风险最大，可能遭受最严重的虐待。就一级预防虐待而言，通常不可行，鉴定影响虐待儿童积极结果的因素至关重要。遗传风险和保护因素似乎在儿童虐待的行为尖叫中起着重要作用。许多最近的研究已经确定了与儿童逆境相互作用的特定基因，从而在成人和儿童中产生严重抑郁症和与焦虑相关的特征的风险。这些包括调节单胺神经传递和神经内分泌功能的基因。基因环境相互作用的一种可能的机制是，风险基因可能会通过改变HPA轴的功能来赋予压力敏感性。大量证据表明，早期逆境动物模型中HPA轴功能的失调。对患有早期虐待病史的儿童和成人进行的越来越多的研究提供了这种压力系统功能障碍的证据（可能反映在夸张或减弱的皮质醇反应中）。临床前和临床研究的融合证据线表明，HPA轴的过度激活可能是有毒的，并导致大脑结构和功能的改变，与重大抑郁症和其他疾病有关。除了持续的早期胁迫的神经内分泌作用外，这种HPA轴的多动症可能部分是由于与该应力轴调节有关的基因变异所致。本应用的目的是确定虐待学龄前儿童行为问题和心理病理学的遗传和神经内分泌预测指标。调节单胺或HPA轴功能的基因将根据与这些行为问题有关的神经途径以及与内部性障碍和虐待的先前经验关联进行检查。此外，我们试图确定HPA轴功能的变化是否介导了这些关系。后续评估将检查这些生物标志物与行为结果之间的前瞻性关系，以及神经内分泌活动与行为的关联的稳定性。这些结果应提供有关虐待儿童情感和行为问题发展的有价值的信息，这些信息可以指导治疗和预防工作以及未来临床研究工作的方向。 公共卫生相关性：拟议的研究旨在阐明虐待儿童的行为问题的神经生物学和社会风险以及保护因素。这项研究的结果可能会洞悉这些脆弱儿童的神经生物学标记和精神病理学机制。这些信息可能有助于未来的治疗和预防工作。