Genetic contributions to deficits in adaptive function in schizophrenia

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、生物和精神异常以及有效预防/治疗相关病理的药理学和心理社会干预之间的关系。我的职业目标是建立一个有效的，跨学科的研究计划，这将提高我们对精神分裂症的理解，贯穿其多层次的病理。本项目将是实现这一目标的重要一步，因为它将采取跨学科的方法来研究精神分裂症的核心特征-适应功能缺陷的分子遗传和神经认知基础。我作为认知神经科学家的博士培训，以及精神病学神经影像学和电生理学的博士后研究，为我提供了研究精神分裂症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训练与遗传学方面的训练结合起来，这将使我能够调查精神分裂症的特定基因和神经认知表型之间的关联。马萨诸塞州综合医院为这种培训提供了理想的环境，因为它联合了许多在神经科学，精神病学和遗传学领域工作的优秀实验室。尽管最近在了解DLPFC的分子生物学方面取得了进展，但该系统导致精神分裂症适应不良行为的神经认知机制尚未得到很好的理解。我们的初步数据表明，DLPFC机制介导特定的现实世界的知识灵活的行为是受损的精神分裂症。该项目的总体目标是研究COMT和MTHFR基因对这些异常的贡献，这些基因已知会影响前额叶功能。我们将通过记录高空间分辨率功能性磁共振成像（fMRI）数据和具有成本效益的电生理（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则参与一种新颖的、生态有效的范式，该范式呈现现实世界目标导向行为，在视频剪辑中传达。公共卫生相关性：这项研究可能澄清两个候选基因对精神分裂症症状的贡献的神经认知解释。这些结果可能会指导未来在精神分裂症遗传风险儿童中获得真实世界知识的研究，最终目标是设计早期干预治疗。它们可能有助于开发一种新的精神分裂症内表型，以帮助寻找这种疾病的易感基因。

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.