Elucidating the effect of Disc1 on neurodevelopment and synaptic transmission

阐明 Disc1 对神经发育和突触传递的影响

• 批准号: 7320508
• 负责人: JOSEPH A GOGOS
• 金额: $ 33.67万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7320508
• 关键词: Address; Affect; Animal Model; Animals; Arts; Behavior; Biochemical; Biological; Biological Assay; Brain; Brain region; Bromodeoxyuridine; Clinical; Data; Development; Disruption; Family; Future; Gene Expression; Genes; Genetic; Genome; Goals; Hippocampus (Brain); Human; Image; In Vitro; Label; Laboratories; Mediating; Mental disorders; Mood Disorders; Mus; Mutation; Neurons; Nuclear; Numbers; PDE4B; Pattern; Physiological; Play; Proteins; Research; Research Personnel; Risk; Role; Schizophrenia; Signal Transduction; Synaptic Transmission; Testing; Time; Work; base; dentate gyrus; design; disease phenotype; drug development; frontal lobe; genetic linkage; genetic risk factor; in vivo; insight; intracellular protein transport; migration; mouse model; neural circuit; neurodevelopment; neurogenesis; phosphoric diester hydrolase; programs; protein localization location; research study

DESCRIPTION (provided by applicant): Recent genetic studies provide strong support for the gene Disrupted-in-Schizophrenia-1 (DISC1) in mental illness. Additional data obtained primarily by in vitro studies suggested that DISC1 may play a key role in neurodevelopment and cell signaling by interacting with other proteins, including nuclear distribution E-like (NUDE-L) protein and phosphodiesterase 4B. Despite recent advances in the study of DISC1 function, several critical issues remain unanswered. We propose to utilize a unique and reliable mouse model that we have established in our laboratory, which closely mimics the translocation observed in an affected family while preserving endogenous proteins levels, in order to facilitate a better understanding of the physiological contribution of DISC1 in normal and abnormal brain development and function in the context of psychiatric disorders. Our main goals are to a) facilitate a better understanding of the contribution of DISC1 in neurodevelopment, as well as in synaptic transmission and plasticity and b) test whether existing in vitro results can be validated in vivo in the mouse model we have established. Our analysis promises to provide valuable insights into the ways DISC1 increases the risk of psychiatric disorders and at the same time provide a well-characterized animal model that can be used to test further hypotheses and facilitate future drug development efforts.

描述（由申请人提供）：最近的遗传研究为精神疾病中的基因破坏了基因中的基因（DISC1）提供了强有力的支持。主要通过体外研究获得的其他数据表明，通过与其他蛋白质相互作用（包括核分布E-like（Nude-L）蛋白和磷酸二酯酶4B），DISC1可能在神经发育和细胞信号传导中起关键作用。尽管Disc1功能研究最近进步，但几个关键问题仍未得到解答。我们建议利用我们在实验室中建立的独特且可靠的小鼠模型，该模型密切模仿受影响家庭中观察到的易位，同时保留内源性蛋白质水平，以便更好地理解DISC1在正常和异常的脑发育和精神疾病背景下的生理贡献。我们的主要目标是a）促进对神经发育中DISC1的贡献的贡献，以及在突触传播和可塑性和b）测试是否可以在我们已经建立的小鼠模型中在体内验证现有的体外结果。我们的分析有望提供有价值的见解，以了解Disc1增加精神疾病风险的方式，同时提供了一个充分的动物模型，可用于检验进一步的假设并促进未来的药物开发工作。