The role of DISC 1 in synapse formation & function in the developing neocortex

描述(申请人提供)：申请人的长期职业目标是发展成为一名研究精神分裂症病因学的独立调查员。为了实现这一目标，申请人(Brady Maher博士)准备了一项导师研究科学家发展奖(KOI)，旨在：1)在研究精神分裂症易感基因的基因表达和分子相互作用的同时，获得重要的分子生物学和宫内电穿孔技术方面的技术和理论培训；2)准备一份竞争性的R01拨款提案，以建立一个独立的研究计划。KOI申请中提议的培训将在职业发展计划的背景下进行。这份职业计划包括著名分子神经学家(Joe LoTurco博士)的指导，以及职业发展实践技能、研讨会和负责任的研究行为的重要培训机会。申请者承诺提供大学的资源和专业知识。康涅狄格州，部门生理学和神经生物学专业。职业生涯规划的研究部分考察了精神分裂症易感基因DISCI在大脑皮层回路发育中的作用。马赫博士的近期目标是发展分子生物学和宫内电穿孔方面的专业知识。这些技术将被用来将DISCI的各种分子结构表达到发育中的哺乳动物大脑中，以确定对皮质回路发育至关重要的分子信号级联。电路发展的变化将用电生理学进行功能测量。拟议的目标将检验DISCI突变导致精神分裂症背后的异常电路形成的假设。这些实验的结果有望增加我们对DISCI对大脑皮质发育影响的理解。这项提案与公共卫生高度相关，因为大约。1%的人口患有精神分裂症。这项提案的结果将确定导致精神分裂症病因的重要分子级联，从而为其治疗提供潜在的治疗靶点。拟议的整体培训将提供一个基础，以便在第三年制定R01建议。公共卫生相关性：本次拨款申请中建议的培训和研究旨在解释候选易感基因DISC1的突变如何影响前额叶皮质的发育。这项建议的结果将为精神分裂症和其他相关疾病的治疗和预防提供潜在的治疗靶点。

DESCRIPTION (provided by applicant): The applicant's long-term career goal is to develop into an independent investigator studying the etiology of schizophrenia. In order to achieve this objective, the applicant (Dr. Brady Maher) has prepared a Mentored Research Scientist Development Award (KOI) designed to: 1) acquire important technical and theoretical training in molecular biology and in utero electroporation techniques, while investigating gene expression and molecular interactions of schizophrenia susceptibility genes; and 2) prepare a competitive R01 grant proposal in order to establish an independent research program. The training proposed in the KOI application will be conducted in the context of a Career Development Plan. This Career Plan incorporates mentoring from an established molecular neuroscientist (Dr. Joe LoTurco),as well as important training opportunities for practical career development skills, workshops and Responsible Conduct of Research. The applicant as the commitment of resources and expertise from the Univ. of Connecticut, Dept. of Physiology and Neurobiology. The research portion of the Career Plan examines the role of DISCI, a schizophrenia susceptibility gene, in the development of cortical circuits. Dr. Maher's immediate goals are to develop an expertise in molecular biology and in utero electroporation. These techniques will be used to express various molecular constructs of DISCI into the developing mammalian brain to identify molecular signaling cascades important for cortical circuit development. Changes in circuit development will be measured functionally with electrophysiology. The proposed aims will test the hypothesis that mutations in DISCI lead to abnormal circuit formation that underlies schizophrenia. The results from these experiments are expected to increase our understanding of the impact that DISCI has on cortical development. This proposal is highly relevant to public health because approx. 1% of the population suffers from schizophrenia. Results from this proposal will identify important molecular cascades responsible for the etiology of schizophrenia and in so doing will provide potential therapeutic targets for its treatment. The overall training proposed will provide a basis upon which to develop a R01 proposal in Year 3. PUBLIC HEALTH RELEVANCE: The training and research proposed in this grant application are designed to explain how mutations in DISC1, a candidate susceptibility gene, affect the development of the prefrontal cortex. The results obtained from this proposal will provide potential therapeutic targets for the treatment and prevention of schizophrenia and other related disorders.