Investigating the molecular mechanisms of microcephaly

项目摘要 该建议旨在解决常染色体隐性遗传性原发性小头畸形的分子机制 （MCPH），一种以大脑体积小和预期寿命缩短为特征的疾病。具体而言，它侧重于 MCPH患者中最常见的两种突变基因，异常纺锤体（Asp）和WD重复序列 蛋白62（WDR 62）。在研究和职业发展方面提供全面的指导培训方案 成立该委员会是为了确保作为独立调查员取得成功。首先，该提案使用了 创新的方法在果蝇，以阐明的分子机制， 疾病，重点是在细胞和组织水平上使用新的遗传和基因分析大脑的高分辨率分析。 成像方法这一阶段将需要培训苍蝇神经生物学，和共同导师谁是领先的专家 已设立了外地办事处来发挥这一作用。第二，Asp和WDR 62的一种新的核功能将 作为MCPH的潜在机制进行研究，结合以前在苍蝇染色质中的研究生培训， 生物学和基因表达与新一代测序技术的新培训。既飞 神经生物学和对这些蛋白质的核功能的研究将朝着长期目标发展 拟议的研究，这是定义一个“MCPH基因网络”，共同有助于适当的 脑容量这将开始在指导阶段的奖励，通过生成工具和试剂，将 在独立阶段取得成功的关键。在Asp和WDR 62突变体中筛选遗传修饰剂 背景也将进行识别候选基因的MCPH基因网络，建立一个坚实的 为今后独立期间的工作奠定基础。此外，职业发展将在整个 指导阶段。美国国立卫生研究院提供关于指导，领导，赠款写作，研究道德和 将与所述研究目标同时完成的联网活动。一个咨询委员会 还设立了审查研究进展，提供建设性的反馈实验， 职业目标指导。总的来说，这项研究和职业发展培训计划将 提供迄今为止最全面的MCPH分析，并解开MCPH的分子基础。 同时确保作为独立调查员在所有阶段取得成功。

Project Summary This proposal seeks to address the molecular mechanisms of autosomal recessive primary microcephaly (MCPH), a disorder characterized by small brain size and reduced life expectancy. Specifically, it focuses on the two most commonly mutated genes in MCPH patients, Abnormal Spindle (Asp) and WD Repeat-Containing Protein 62 (WDR62). A comprehensive, mentored training regimen in both research and career development has been established in order to ensure success as an independent investigator. First, this proposal uses an innovative approach in Drosophila melanogaster in order to elucidate the molecular mechanisms of the disorder, focusing on high resolution analysis of brains at the cell and tissue level using novel genetic & imaging methods. This phase will require training in fly neurobiology, and a co-mentor who is a leading expert in the field has been established to serve in this role. Secondly, a novel nuclear function for Asp & WDR62 will be investigated as the underlying mechanism of MCPH, combining previous graduate training in fly chromatin biology and gene expression with new training in next-generation sequencing technologies. Both the fly neurobiology and investigation into the nuclear function of these proteins will build towards the long term goals of the proposed research, which is to define an `MCPH gene network' that collectively contributes to proper brain size. This will begin during the mentored phase of the award by generating tools & reagents that will be critical for success during the independent phase. A genetic modifier screen in the Asp and WDR62 mutant background will also be carried out to identify candidate genes in the MCPH gene network, establishing a solid foundation for future work during independence. Additionally, career development will continue throughout the mentored phase. The NIH provides workshops on mentorship, leadership, grant writing, research ethics and networking activities which will be completed in parallel with the stated research goals. An advisory committee has also been established to review research progress, provide constructive feedback on experiments and guidance on career objectives. Collectively, this training plan in both research and career development will provide the most comprehensive analysis of MCPH to date and unlock the molecular underpinnings of the disorder while ensuring success in all phases as an independent investigator.