Modeling Reciprocal Genomic Disorders in Neuronal Cells and Cerebral Organoids

神经元细胞和脑类器官中相互基因组疾病的建模

• 批准号: 10377357
• 负责人: Alexander Nuttle
• 金额: $ 11.03万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377357
• 关键词: 16p11.2; 1q21; Address; Affect; Attention deficit hyperactivity disorder; Biological; Bipolar Disorder; Brain; Cell Line; Cell model; Cells; Cerebrum; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Disease; Disease model; Doctor of Philosophy; Exhibits; Experimental Models; Faculty; Female; Gene Deletion; Gene Expression Profile; Gene Expression Profiling; General Hospitals; Genes; Genetic; Genetic Predisposition to Disease; Genetic Recombination; Genetic Variation; Genetic study; Genome engineering; Genomic Segment; Genomic medicine; Genomics; Hand; Head; Head circumference; Human; Human Genetics; Immunofluorescence Immunologic; Individual; Institutes; Intellectual functioning disability; Laboratories; Learning; Length; Link; Macrocephaly; Massachusetts; Measurement; Meiosis; Mentors; Mentorship; Methods; Microcephaly; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Morphology; Mutation; Neurites; Neurodevelopmental Disorder; Neurology; Neuronal Differentiation; Neurons; Organoids; Other Genetics; Overlapping Genes; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phase; Phenotype; Physical shape; Positioning Attribute; Precision therapeutics; RNA; Recurrence; Research; Research Personnel; Research Training; Resources; Schizophrenia; Source; Symptoms; Syndrome; Technology; Time; Training; Training Programs; Translating; Universities; ZIKV infection; autism spectrum disorder; base; career; career development; cell type; clinical heterogeneity; co-infection; collaborative environment; disability; dosage; functional genomics; gene network; genetic architecture; genome sciences; genome-wide; human disease; human model; induced pluripotent stem cell; innovation; insight; male; mid-career faculty; nerve stem cell; neurodevelopment; neuropsychiatric disorder; novel; post-doctoral training; professor; programs; psychogenetics; regenerative biology; single cell analysis; single-cell RNA sequencing; skills; stem cell biology; stem cells; tool; transcriptome sequencing; transcriptomics

Abstract The proposed research and training program will prepare Dr. Xander Nuttle to become an independent investigator focused on human genetics and neurodevelopmental genomics. Dr. Nuttle obtained a Ph.D. in Genome Sciences, investigating genes specifically duplicated along the human lineage, and has dedicated his postdoctoral training to the development of innovative methods of genome engineering in relation to human reciprocal genomic disorders (RGDs). He now seeks to develop new expertise in functional genomics by leveraging emerging stem-cell, single-cell, organoid, and genome engineering technologies to characterize mutations linked to neurodevelopmental disorders. The training program consists of two phases: two years acquiring new skills primarily through mentored research, followed by three years establishing an independent laboratory. The research plan incorporates both experimental and computational approaches, modeling RGDs in neuronal cells and cerebral organoids to gain insights into mechanisms of pathogenesis. Dr. Michael Talkowski, Associate Professor of Neurology at the Center for Genomic Medicine (CGM) at Massachusetts General Hospital (MGH), will serve as the primary mentor. Dr. Kevin Eggan, Professor of Stem Cell and Regenerative Biology at Harvard University, will provide complementary expertise as a co-mentor. The mentor and co-mentor are world leaders in psychiatric genetics, functional genomics, and cellular disease modeling. To supplement their mentorship, a team of investigators at various career stages will provide Dr. Nuttle with targeted training and career development advice. The CGM at MGH, Harvard, and the Broad Institute form a highly collaborative environment ideally positioned to support Dr. Nuttle’s transition to independence. Here, he will have access to abundant resources and tools and a wealth of diverse scientific and clinical expertise. RGDs are among the most common genetic subtypes of autism spectrum disorder, schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, and intellectual disability. All RGDs involve recurrent deletions and duplications of particular genomic segments, yet the molecular details of how these dosage changes confer disease are not well understood. To address this challenge, we will (1) examine transcriptional signatures and neurite dynamics in RGD neuronal cellular models; (2) generate and characterize RGD cerebral organoid models; and (3) integrate high-throughput genome engineering with cellular modeling to identify driver genes underlying RGD-associated neurite phenotypes. This research will immerse Dr. Nuttle in several cutting-edge fields, giving him the opportunity to learn functional genomics, single-cell analysis, and brain organoid modeling. With these skills in hand, he will be able to functionally characterize genetic variation affecting neurodevelopment and be well-positioned to launch a productive independent research program.

摘要 拟议的研究和培训计划将为Xander Nuttle博士成为一名独立的 研究人员专注于人类遗传学和神经发育基因组学。纳特尔博士于年获得博士学位。 基因组科学，研究人类谱系中特定复制的基因，并致力于他的 博士后培训，以开发与人类有关的基因组工程创新方法 互惠基因组病(RGDS)。他现在寻求在功能基因组学方面开发新的专业知识 利用新兴的干细胞、单细胞、有机体和基因组工程技术来表征 突变与神经发育障碍有关。培训计划分为两个阶段：两年 主要通过有指导的研究获得新技能，然后三年建立一个独立的 实验室。 研究计划结合了实验和计算方法，对RGDS进行了建模 神经细胞和脑器官，以深入了解发病机制。迈克尔博士 Talkowski，马萨诸塞州基因组医学中心(CGM)神经学副教授 综合医院(MGH)将担任主要导师。凯文·埃根博士，干细胞和 哈佛大学再生生物学将作为共同导师提供补充专业知识。良师益友 和共同导师在精神病学遗传学、功能基因组学和细胞疾病建模方面处于世界领先地位。 为了补充他们的指导，一个处于不同职业阶段的调查团队将为纳特尔博士提供 有针对性的培训和职业发展建议。麻省理工学院、哈佛大学和布罗德研究所的CGM组成了一个 高度协作的环境非常适合支持纳特尔博士向独立的过渡。在这里，他 将获得丰富的资源和工具以及丰富的科学和临床专业知识。 RGDS是自闭症谱系障碍、精神分裂症、 双相情感障碍、注意力缺陷/多动障碍和智力残疾。所有RGD都与复发性有关 特定基因组片段的缺失和复制，但这些剂量的分子细节 导致疾病的变化还没有被很好地理解。为了应对这一挑战，我们将(1)检查转录 RGD神经元细胞模型中的信号和轴突动力学；(2)RGD的产生和表征 脑器官模型；以及(3)将高通量基因组工程与细胞建模相结合，以 确定RGD相关轴突表型的驱动基因。这项研究将使纳特尔博士沉浸在 几个前沿领域，使他有机会学习功能基因组学、单细胞分析和 脑器官模型。掌握了这些技能，他将能够从功能上描述基因变异 影响神经发育，并处于有利地位，以启动富有成效的独立研究计划。