Genetic contributions to deficits in adaptive function in schizophrenia

遗传对精神分裂症适应功能缺陷的影响

• 批准号: 7885452
• 负责人: Tatiana Sitnikova
• 金额: $ 18.58万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-06 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885452
• 关键词: Activities of Daily Living; Behavior; Biological; Biological Assay; Candidate Disease Gene; Child; Clip; Cognitive; Community Integration; Comprehension; Data; Diagnostic; Disease; Dopamine; Early treatment; Electrophysiology (science); Elements; Environment; Environmental Risk Factor; Fellowship; Functional Magnetic Resonance Imaging; Future; General Hospitals; Genes; Genetic; Genetic Risk; Genotype; Goals; Knowledge; Knowledge acquisition; Laboratories; MTHFR gene; Mediating; Molecular Biology; Molecular Genetics; Neurocognitive; Neurosciences; Participant; Pathology; Patients; Performance; Phenotype; Postdoctoral Fellow; Prevention; Process; Psyche structure; Psychiatry; Relative (related person); Research; Resolution; Schizophrenia; Severities; Subgroup; Susceptibility Gene; Symptoms; System; Training; Work; attenuation; base; behavioral impairment; career; cost; design; effective intervention; endophenotype; flexibility; improved; information organization; meetings; methionylmethionine; neuroimaging; neuropsychiatry; novel; programs; psychosocial; public health relevance; valylvaline

DESCRIPTION (provided by applicant): The ultimate goals of schizophrenia research are to achieve understanding of the relationships between its genetic and environmental risk factors, biological and mental abnormalities, and pharmacological and psychosocial interventions effective in prevention/treatment of associated pathology. My career goal is to establish an effective, inter-disciplinary research program that will improve our understanding of schizophrenia throughout its multiple levels of pathology. The present project will be an important step toward this goal because it will take an inter-disciplinary approach to examine molecular genetic and neurocognitive bases of a core feature of schizophrenia - deficits in adaptive function. My doctoral training as a cognitive neuroscientist, followed by a post-doctoral fellowship in psychiatric neuroimaging and electrophysiology, have provided me with the necessary expertise to study neurocognitive phenotypes of schizophrenia. I now wish to integrate my training in neuropsychiatry with training in genetics that will enable me to investigate the association between specific genes and neurocognitive phenotypes of schizophrenia. Mass. General Hospital provides an ideal environment for this training as it unites a number of outstanding laboratories working in neuroscience, psychiatry, and genetics. Despite recent progress in understanding the molecular biology of the DLPFC, the neurocognitive mechanisms by which this system contributes to maladaptive behavior in schizophrenia are not yet well understood. Our preliminary data suggest that DLPFC mechanisms mediating specific real-world knowledge critical for flexible behavior are impaired in schizophrenia. The overall goal of this project is to examine contributions of COMT and MTHFR genes, known to influence prefrontal function, to these abnormalities. We will assay target neurocognitive mechanisms by recording high spatial resolution functional magnetic resonance imaging (fMRI) data and cost-effective electrophysiological (ERR) data while schizophrenia patients and healthy controls participate in a novel, ecologically valid paradigm that presents real-world goal- directed behaviors, conveyed in video clips. PUBLIC HEALTH RELEVANCE: This study may clarify the neurocognitive interpretation of the contributions of two candidate genes to the symptoms of schizophrenia. The results may direct future research of real-world knowledge acquisition in children at genetic risk for schizophrenia, with an ultimate goal to design early intervention treatments. They may help to develop a new endophenotype of schizophrenia to assist search for susceptibility genes of this disorder.

描述（由申请人提供）：精神分裂症研究的最终目标是了解其遗传和环境风险因素，生物学和精神异常以及有效预防/治疗相关病理的药理和心理社会干预措施之间的关系。我的职业目标是建立一个有效的，跨学科的研究计划，该计划将在其多种层次的病理学层面上提高我们对精神分裂症的理解。本项目将是朝着这一目标迈出的重要一步，因为它将采用跨学科的方法来检查精神分裂症的核心特征的分子遗传和神经认知碱 - 自适应功能缺陷。我作为认知神经科学家的博士培训，然后是精神神经影像学和电生理学的博士后研究金，为我提供了研究精神分裂症的神经认知表型的必要专业知识。我现在希望将我在神经精神病学方面的培训与遗传学培训相结合，这将使我能够研究精神分裂症的特定基因与神经认知表型之间的关联。马萨诸塞州综合医院为这项培训提供了理想的环境，因为它结合了许多从事神经科学，精神病学和遗传学工作的杰出实验室。尽管在理解DLPFC的分子生物学方面最近取得了进展，但该系统促进精神分裂症中适应不良行为的神经认知机制尚未得到充分了解。我们的初步数据表明，在精神分裂症中，介导对柔性行为至关重要的特定现实世界知识的DLPFC机制受到了损害。该项目的总体目标是检查COMT和MTHFR基因的贡献，已知会影响前额叶功能对这些异常。我们将通过记录高空间分辨率功能磁共振成像（fMRI）数据和具有成本效益的电生理学（ERR）数据来分析目标神经认知机制，而精神分裂症患者和健康对照组则参与了一种新颖的生态有效的范式，该范式表现出了现实的目标行为，可以在视频中提供现实的目标行为。公共卫生相关性：这项研究可能阐明了两个候选基因对精神分裂症症状的贡献的神经认知解释。该结果可能会导致对儿童的现实知识获取的未来研究，以对精神分裂症的遗传风险进行研究，并以设计早期干预治疗的最终目标。它们可能有助于开发一种新的精神分裂症内表型，以帮助搜索这种疾病的易感基因。