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Investigating the molecular mechanisms of microcephaly

研究小头畸形的分子机制

基本信息

批准号：
10361477
负责人：
Todd Schoborg
金额：
$ 24.9万
依托单位：
UNIVERSITY OF WYOMING
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10361477
关键词：
Address Advisory Committees Affect Animals Architecture Autosomal recessive primary microcephaly Award Behavior Behavior Control Binding Binding Sites Biology Brain Brain region Candidate Disease Gene Cell Nucleus Cell division Cells Cellular biology Centrosome Chromatin Chromatin Structure Clinical Data Defect Development Disease Disease model Drosophila genus Drosophila melanogaster Educational workshop Ensure Evolution Feedback Foundations Future Gene Expression Genes Genetic Genetic Epistasis Genetic Screening Genetic Transcription Goals Grant Growth Head Individual Interphase Intuition Investigation Knowledge Lead Leadership Life Expectancy Link Longevity Maps Measurement Measures Mentors Mentorship Microcephaly Microtubules Mitosis Mitotic Mitotic spindle Modeling Molecular Mutate Mutation Neurobiology Neurodevelopmental Disorder Neuroglia Neurons Nuclear Orthologous Gene Pathway interactions Patients Phase Phenotype Population Protein Fragment Proteins Reagent Regimen Research Research Ethics Research Personnel Resolution Role Solid Standardization Technology Testing Tissues Training Transgenes United States National Institutes of Health WD Repeat Work Writing brain cell brain morphology brain size brain volume career career development comparative design experimental study fly gene function gene network human disease imaging genetics imaging modality innovation mind control mutant neuron apoptosis next generation sequencing novel protein function research and development success tool

项目摘要

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.

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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Whole Animal Imaging of Drosophila melanogaster using Microcomputed Tomography.

DOI：
10.3791/61515
发表时间：
2020-09-02
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Schoborg TA
通讯作者：
Schoborg TA

Computed tomography with segmentation and quantification of individual organs in a D. melanogaster tumor model.

DOI：
10.1038/s41598-022-05991-5
发表时间：
2022-02-08
期刊：
Scientific reports
影响因子：
4.6
作者：
Holland P;Quintana EM;Khezri R;Schoborg TA;Rusten TE
通讯作者：
Rusten TE

Host autophagy mediates organ wasting and nutrient mobilization for tumor growth.

DOI：
10.15252/embj.2020107336
发表时间：
2021-09-15
期刊：
The EMBO journal
影响因子：
0
作者：
Khezri R;Holland P;Schoborg TA;Abramovich I;Takáts S;Dillard C;Jain A;O'Farrell F;Schultz SW;Hagopian WM;Quintana EM;Ng R;Katheder NS;Rahman MM;Teles Reis JG;Brech A;Jasper H;Rusan NM;Jahren AH;Gottlieb E;Rusten TE
通讯作者：
Rusten TE

The neurodevelopmental transcriptome of the Drosophila melanogaster microcephaly gene abnormal spindle reveals a role for temporal transcription factors and the immune system in regulating brain size.

果蝇小头畸形基因异常纺锤体的神经发育转录组揭示了时间转录因子和免疫系统在调节大脑大小中的作用。

DOI：
10.1101/2023.01.09.523369
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Mannino,MariaC;BartelsCassidy,Mercedes;Florez,Steven;Rusan,Zeid;Chakraborty,Shalini;Schoborg,Todd
通讯作者：
Schoborg,Todd