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博士成为独立研究人员专注于人类遗传学和神经发育基因组学。 Nuttle博士获得了博士学位在基因组科学，调查了沿着人类谱系专门复制的基因，并致力于他与人类有关的创新方法开发创新方法的博士后培训相互基因组疾病（RGD）。他现在寻求通过功能基因组学方面的新专业知识利用新兴的干细胞，单细胞，器官和基因组工程技术来表征与神经发育障碍有关的突变。培训计划包括两个阶段：两年主要通过指导的研究获得新技能，然后建立独立的三年实验室。研究计划既包含了实验和计算方法，又将RGD建模神经元细胞和大脑器官，以洞悉发病机理。迈克尔博士马萨诸塞州基因组医学中心（CGM）神经病学副教授Talkowski 综合医院（MGH）将担任主要导师。干细胞教授Kevin Eggan博士哈佛大学的再生生物学将提供完整的专业知识。精神和同事是精神遗传学，功能基因组学和细胞疾病建模的世界领导者。为了补充他们的心态，在各个职业阶段的一个调查人员团队将为Nuttle博士提供有针对性的培训和职业发展建议。 MGH，哈佛大学和Broad Institute的CGM成立A 高度协作的环境理想地是支持Nuttle博士向独立的过渡。在这里，他将可以使用丰富的资源和工具以及大量的科学和临床专业知识。 RGD是自闭症谱系障碍的最常见遗传亚型之一，精神分裂症，双相情感障碍，注意力缺陷/多动症和知地残疾。所有RGD都涉及经常性特定基因组段的删除和重复，但是这些剂量如何的分子细节变化会议疾病尚不清楚。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特征和神经动力学；（2）生成和表征RGD 大脑器官模型；（3）与细胞建模的集成高通量基因组工程鉴定与RGD相关的神经蛋白表型的基因。这项研究将使Nuttle博士沉浸在几个尖端领域，使他有机会学习功能基因组学，单细胞分析和脑器官建模。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，并有充分的位置，以启动一项富有成效的独立研究计划。