Somatic mutations in neurodevelopment and disease

神经发育和疾病中的体细胞突变

• 批准号: 10506193
• 负责人: Diane D Shao
• 金额: $ 19.6万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10506193
• 关键词: Address; Advisory Committees; Affect; Algorithms; Area; Automobile Driving; Autopsy; Awareness; Bioinformatics; Biological Sciences; Boston; Brain; Candidate Disease Gene; Cell Cycle; Cell division; Cells; Cellular biology; Child; Childhood Neurological Disorder; Clinical; Communities; Cortical Dysplasia; DNA; Data; Detection; Development; Developmental Process; Diagnosis; Disease; Epilepsy; Evaluation; Future; Genes; Genetic; Genome; Genomic medicine; Genotype; Goals; Heritability; Hospital Departments; Human; Human Development; Human Genetics; Individual; Institutes; Investigation; Laboratories; Lead; Life; Longevity; Malignant Neoplasms; Medical; Medical Genetics; Mental disorders; Mentors; Methods; Molecular and Cellular Biology; Mosaicism; Mutation; Mutation Analysis; Neoplasms; Nerve Degeneration; Neurology; Neurons; Neurosciences; Pattern; Pediatric Hospitals; Phenotype; Physicians; Population Attributable Risks; Pregnancy; Prevalence; Publishing; Research; Research Personnel; Research Training; Resources; Risk; Scientist; Single Nucleotide Polymorphism; Somatic Mutation; Statistical Data Interpretation; Technology; Time; Tissues; Training; Variant; analytical method; autism spectrum disorder; base; brain malformation; career; childhood epilepsy; clinical application; clinical practice; cohort; exome; exome sequencing; experience; fetal; gene discovery; genome sequencing; hemimegalencephaly; human fetal brain; infancy; innovative technologies; insight; medical schools; nerve stem cell; nervous system disorder; neurodevelopment; neurogenetics; novel; postnatal; rate of change; skills; tool; whole genome

PROJECT SUMMARY Somatic post-zygotic mutations are increasingly recognized as a cause of neurologic disorders ranging from epilepsy to autism to neurodegeneration. Somatic mutations accumulate with each cell division during fetal life, a developmental process of not yet fully defined scale and mechanism, hampering interpretation of disease states. The first part of this study implements a clinically applicable somatic-aware algorithm to identify early somatic mutations that lead to epilepsy and brain malformations. The latter aspect applies cutting-edge single- cell DNA technology to human fetal brain in order to define the rates and mechanisms driving accumulation of somatic mutations in neurons during normal development. The insights from this study have the potential to impact the detection and diagnosis of somatic disorders in clinical practice, and defines the scope of normal brain developmental mosaicism in neurons to serve as a framework for future studies of neurological disease. The candidate’s career goal is to become an independent physician-scientist contributing to the understanding of genetic and functional implications of post-zygotic mutations in childhood neurological disorders. The candidate trained clinically in child neurogenetics with deep research experience, including in cellular and molecular biology and statistical analysis, acquired in the cancer field. During the mentored training period, the candidate will prioritize activities to transition skills from a cancer background to human genetics and neuroscience: specifically working with primary human postmortem tissue, single cell analytical methods, and evaluating genotype-phenotype relationships in somatic disorders, and additionally, preparing for a transition to independence. The candidate will be mentored by Dr. Christopher Walsh, a renowned neurobiologist who has mentored dozens of successful independent investigators and will be supported by an advisory team with expertise in epilepsy, neuroscience, and bioinformatics. The proposed research and training plan will take place in the laboratory of Dr. Walsh at Boston Children’s Hospital (BCH), which is affiliated with Harvard Medical School and Howard Hughes Medical Institute, embedded within a world-class life sciences community of the Boston- Cambridge area. The candidate will benefit from both the outstanding resources and intellectual community of this tremendous network in addition to the close-knit communities within the BCH Department of Neurology and Division of Genetics.

项目概要 体细胞合子后突变越来越被认为是神经系统疾病的原因，包括 癫痫、自闭症、神经退行性疾病，体细胞突变随着胎儿生命中的每次细胞分裂而积累， 尚未完全确定规模和机制的发育过程，阻碍了对疾病的解释 这项研究的第一部分实施了一种临床适用的体细胞感知算法来识别早期。 导致癫痫和脑畸形的体细胞突变应用了尖端的单基因突变技术。 细胞 DNA 技术应用于人类胎儿大脑，以确定驱动积累的速率和机制 这项研究的见解有可能在正常发育过程中神经元的体细胞突变。 影响临床实践中躯体疾病的检测和诊断，并定义正常范围 神经元中的大脑发育镶嵌现象可作为未来神经系统疾病研究的框架。 候选人的职业目标是成为一名独立的医师科学家，为人类健康做出贡献 了解儿童神经系统合子后突变的遗传和功能影响 该候选人接受过儿童神经遗传学方面的临床培训，具有丰富的研究经验，包括在 在指导培训期间获得的细胞和分子生物学以及统计分析。 在此期间，候选人将优先考虑将技能从癌症背景过渡到人类遗传学和 神经科学：专门研究人类死后原代组织、单细胞分析方法，以及 评估躯体疾病中的基因型-表型关系，此外，为向 候选人将受到著名神经生物学家克里斯托弗·沃尔什博士的指导。 指导了数十名成功的独立调查员，并将得到咨询团队的支持 拟议的研究和培训计划将在癫痫、神经科学和生物信息学方面进行。 哈佛医学院附属波士顿儿童医院 (BCH) Walsh 博士的实验室 和霍华德休斯医学研究所，嵌入波士顿的世界级生命科学社区- 候选人将受益于剑桥地区的优秀资源和知识社区。 除了 BCH 神经病学部门内紧密联系的社区之外，还有这个庞大的网络 遗传学部。