Investigating the molecular mechanisms of microcephaly

项目摘要 本研究旨在探讨常染色体隐性遗传性原发性小头畸形的分子机制。 (MCPH)，一种以脑体积小和预期寿命缩短为特征的疾病。具体地说，它侧重于 MCPH患者最常见的两种突变基因：纺锤体异常(Asp)和WD重复序列 蛋白62(WDR62)。在研究和职业发展方面的全面、有指导的培训方案 为了确保作为独立调查员的成功，已经成立了一个独立调查员小组。首先，该提案使用了 在黑腹果蝇中的创新方法，以阐明其分子机制 无序，专注于使用新的遗传和组织水平的高分辨率大脑分析 成像方法。这一阶段将需要苍蝇神经生物学方面的培训，以及一位领先的专家的共同导师 已经建立了在外地服务的这一角色。其次，Asp&WDR62的一个新的核功能将 结合以往对苍蝇染色质的研究生训练，研究MCPH的潜在机制 生物学和基因表达与下一代测序技术的新培训。两只苍蝇 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。 这项拟议的研究的目的是定义一个共同有助于适当的 大脑的大小。这将在授奖的指导阶段通过生成工具和试剂开始，这些工具和试剂将 对独立阶段的成功至关重要。天冬氨酸和WDR62突变体中的一个遗传修饰物筛选 还将开展背景研究，寻找MCPH基因网络中的候选基因，建立坚实的 在独立期间为今后的工作奠定基础。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导师、领导力、拨款撰写、研究伦理和 将与所述研究目标并行完成的联网活动。咨询委员会 还建立了审查研究进展情况、对实验提供建设性反馈以及 关于职业目标的指导。总的来说，这项研究和职业发展方面的培训计划将 提供迄今为止对MCPH的最全面的分析，并解开 作为一名独立的调查员，在确保所有阶段取得成功的同时，也要确保混乱。

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.