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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的拟议的研究和培训计划将使 Xander Nuttle 博士成为一名独立的 Nuttle 博士专注于人类遗传学和神经发育基因组学，并获得了博士学位。基因组科学，研究沿着人类谱系专门复制的基因，并致力于研究开发与人类相关的基因组工程创新方法的博士后培训他现在寻求通过功能基因组学发展新的专业知识。利用新兴的干细胞、单细胞、类器官和基因组工程技术来表征与神经发育障碍相关的突变该培训计划分为两个阶段：两年。主要通过指导研究获得新技能，然后用三年时间建立一个独立的实验室。该研究计划结合了实验和计算方法，对 RGD 进行建模神经元细胞和大脑类器官，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) 神经病学副教授综合医院 (MGH) 干细胞教授 Kevin Eggan 博士将担任主要导师。哈佛大学再生生物学系将作为共同导师提供补充专业知识。和共同导师是精神遗传学、功能基因组学和细胞疾病建模领域的世界领先者。为了补充他们的指导，处于不同职业阶段的研究人员团队将为 Nuttle 博士提供 MGH、哈佛大学和布罗德研究所的 CGM 形成了有针对性的培训和职业发展建议。高度协作的环境非常适合支持纳特尔博士向独立过渡。将获得丰富的资源和工具以及丰富的多样化科学和临床专业知识。 RGD 是自闭症谱系障碍、精神分裂症、双相情感障碍、注意力缺陷/多动障碍和智力障碍所有 RGD 都涉及复发性障碍。特定基因组片段的删除和重复，但这些剂量的分子细节为了应对这一挑战，我们将（1）检查转录。 (2) 生成并表征 RGD 脑类器官模型；(3) 将高通量基因组工程与细胞建模相结合确定 RGD 相关神经突表型的驱动基因这项研究将使 Nuttle 博士沉浸其中。多个前沿领域，使他有机会学习功能基因组学、单细胞分析和有了这些技能，他将能够在功能上表征遗传变异。影响神经发育，并有能力启动富有成效的独立研究计划。