Gene-Environment Interactions /Neuropsychiatric Disorder

基因-环境相互作用/神经精神疾病

• 批准号: 7019718
• 负责人: JAY A GINGRICH
• 金额: $ 33.09万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-10 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7019718
• 关键词: behavior test; behavioral genetics; disease /disorder etiology; early experience; gene environment interaction; genetic models; genetic polymorphism; genetic promoter element; genetic susceptibility; genetic transcription; genotype; hippocampus; hypothalamic pituitary adrenal axis; laboratory mouse; mental disorders; mother deprivation; neurogenesis; neurogenetics; neuroregulation; pathologic process; phenotype; psychological stressor; serotonin transporter; stress

DESCRIPTION (provided by applicant): Different lines of evidence support the notion that psychiatric disorders result from the interaction of vulnerability genes and environmental factors. The incomplete penetrance (discordance) of psychiatric disorders in identical twins has been hypothesized to be the result of environmental influences. Likewise, genetic differences have been postulated to be responsible for the seeming resilience or vulnerability to psychiatric symptoms seen in subjects exposed to similar environmental situations. Although this gene- environment diathesis of psychiatric disorders has intuitive appeal, neither the genes conferring susceptibility nor the environmental factors that increase the risk of psychiatric morbidity are well understood. Recently some progress has been made in identifying both susceptibility genes and environmental factors that may influence the outcome in major depression, the most common psychiatric disorder that takes an enormous toll on individuals, their families, and society. A highly influential study by Caspi demonstrated that certain promoter variants of the serotonin transporter gene (5HTT) interact with either early life stress (childhood maltreatment) or adult stresses (job loss, divorce, etc.) to modulate the likelihood of depressive symptoms, diagnosed major depression, and suicidal behavior in the study subjects. Specifically, the study found that promoter variants that reduce transcriptional efficiency of the 5HTT increase depression-related phenotypes whereas variants that have higher expression confer resilience to childhood or adult stresses. The availability of a mouse model of a 5HTT-environment interaction allows us to ask several specific questions regarding the positive and negative ways that the environment may be manipulated to reduce or increase the expression of depression-related behaviors. In addition, a mouse model offers the possibility to investigate the neural substrates that mediate the environmental impact on behavior. This line of investigation offers the possibility of gaining new understanding regarding the pathogenesis of depressive disorders.

描述（申请人提供）：不同的证据线支持了以下观点：精神疾病是由于脆弱性基因和环境因素的相互作用而引起的。假设相同双胞胎中精神疾病的不完全渗透性（不一致）是环境影响的结果。同样，已经假定遗传差异是导致在暴露于类似环境情况的受试者中看到的韧性或对精神病症状的脆弱性。尽管这种基因环境对精神疾病的素养具有直观的吸引力，但赋予易感性的基因也不是增加精神病发病风险的环境因素。最近，在确定可能影响严重抑郁症结果的易感基因和环境因素方面取得了一些进展，这是最常见的精神疾病，对个人，家人和社会造成了巨大损失。 CASPI的一项高度影响力的研究表明，5-羟色胺转运蛋白转运蛋白基因（5HTT）的某些启动子变异与早期生命压力（儿童虐待）或成人压力（失业，离婚等）相互作用，以调节抑郁症状的可能性，诊断为抑郁症和自杀行为。具体而言，该研究发现，降低5HTT转录效率的启动子变体会增加与抑郁症相关的表型，而具有较高表达的变体具有更高的表达能力对儿童或成人压力的弹性。 5HTT-环境相互作用的小鼠模型的可用性使我们能够对可能被操纵环境的正面和负面方式提出几个特定问题，以减少或增加与抑郁症相关行为的表达。此外，小鼠模型还提供了研究介导环境对行为影响的神经底物的可能性。这一调查提供了有关抑郁症发病机理的新理解的可能性。