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

描述（由申请人提供）：申请人的长期职业目标是成为一名研究精神分裂症病因学的独立研究者。为了实现这一目标，申请人（Brady Maher博士）准备了一个指导研究科学家发展奖（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，获得分子生物学和子宫电穿孔技术方面的重要技术和理论培训；2)准备一个有竞争力的R01拨款提案，以建立一个独立的研究计划。KOI申请书中提议的培训将在职业发展计划的范围内进行。该职业规划包括来自知名分子神经科学家（Joe LoTurco博士）的指导，以及实用职业发展技能、研讨会和负责任的研究行为的重要培训机会。康涅狄格大学生理学和神经生物学学系提供资源和专业知识。职业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。Maher博士的近期目标是发展分子生物学和子宫电穿孔方面的专业知识。这些技术将用于在发育中的哺乳动物大脑中表达DISCI的各种分子结构，以鉴定对皮质回路发育重要的分子信号级联。电路发育的变化将通过电生理学功能测量。提出的目标将验证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对皮质发育的影响的理解。这项建议与公共卫生高度相关，因为大约。1%的人患有精神分裂症。这项提议的结果将确定负责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。建议的整体培训将为第三年制定R01提案提供基础。公共卫生相关性：本拨款申请中提出的培训和研究旨在解释DISC1（一种候选易感基因）的突变如何影响前额皮质的发育。本研究结果将为精神分裂症及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.