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(申请人提供)：儿童期虐待，以虐待和忽视的形式，是一个主要的公共卫生问题。受虐待的儿童有更高的内在化精神病理学的比率，并有很高的风险产生广泛的不良后果。婴幼儿受到虐待的风险最大，可能遭受最严重的虐待。由于虐待的初级预防往往是不可行的，确定影响虐待儿童积极结果的因素是至关重要的。遗传风险和保护因素似乎在儿童期虐待的行为尖叫中发挥了重要作用。最近的一些研究已经确定了与童年逆境相互作用的特定基因，这些基因会在成人和儿童中产生与主要抑郁和焦虑相关的特征的风险。这些基因包括调节单胺类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机制是，风险基因可能通过改变HPA轴的功能来增强对压力的敏感性。大量证据证明，在早期逆境的动物模型中，HPA轴功能失调。越来越多对有早期虐待史的儿童和成人的研究提供了这种应激系统功能障碍的证据(这可能反映在皮质醇反应的夸大或减弱上)。来自临床前和临床研究的一系列证据表明，HPA轴的过度激活可能是有毒的，并导致与严重抑郁症和其他疾病有关的回路中大脑结构和功能的改变。除了忍受早期应激的神经内分泌影响外，这种HPA轴过度活动可能部分是由于参与调节该应激轴的基因变异造成的。本应用的目的是确定受虐待的学龄前儿童行为问题和精神病理学的遗传和神经内分泌预测因子。调节单胺或HPA轴功能的基因将基于与这些行为问题有关的神经通路的参与以及与内在化障碍和虐待的先前经验联系而进行检查。此外，我们试图确定HPA轴功能的改变是否调节了这些关系。后续评估将检查这些生物标记物和行为结果之间的预期关系，以及神经内分泌活动与行为相关性的稳定性。这些结果应该提供有关受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，并为未来的临床研究工作提供方向。 公共卫生相关性：这项拟议的研究试图阐明虐待儿童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为深入了解这些易受伤害儿童的神经生物学标志物和精神病理机制提供帮助。这些信息可能有助于今后的治疗和预防工作。