Investigating the Role of Somatic Mutations in Neurofibromatosis Brain

研究体细胞突变在神经纤维瘤病脑中的作用

基本信息

批准号：
10722624
负责人：
Daniel Snellings
金额：
$ 7.01万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10722624
关键词：
Address Adult Age Area Attention Automobile Driving Biological Assay Brain Cell Nucleus Cells Central Nervous System Characteristics Child Childhood Chromosomal Rearrangement Copy Number Polymorphism DNA Data Deamination Foundations Freezing Future Genes Genetic Glioma Heterozygote Human Impaired cognition Impairment Individual Intellectual functioning disability Knowledge Lead Life Loss of Heterozygosity Mediating Memory impairment Methods Mosaicism Mus Mutagenesis Mutation Mutation Analysis Mutation Spectra NF1 gene Neurofibromatoses Neurofibromatosis 1 Neuroglia Neurologic Deficit Neurons Oligodendroglia Oncogenes Pathogenesis Pattern Perception Peripheral Nervous System Phenotype Predisposition Preparation Role Sampling Schizophrenia Somatic Mutation Syndrome Testing United States National Institutes of Health Variant Work autism spectrum disorder autosome biobank cancer predisposition cell type cognitive function driving force executive function gamma-Aminobutyric Acid genome sequencing genome-wide inhibitory neuron innovative technologies insight mind control mosaic variant mouse model neoplastic cell nervous system disorder neurobehavioral tumor whole genome

项目摘要

PROJECT SUMMARY Neurofibromatosis type 1 (NF) is an autosomal dominant cancer predisposition syndrome characterized by tumors that form throughout the central and peripheral nervous systems. In addition to tumors, ~80% of individuals with NF have neurological deficits including impairment of memory, attention, perception, and executive functioning. Previous work has established the importance of somatic mutations-post-zygotic changes to DNA that only exist in a subset of cells-for tumor formation in NF. Despite the critical importance of somatic mutation in NF pathogenesis and the deep study of particular mutations that drive tumor formation, the overall dynamics of somatic mutagenesis is poorly understood. Do individuals with NF have a higher burden of somatic mutations compared to unaffected individuals? Do infrequent somatic mutations in neurons contribute to the neurological deficits in NF? What genetic mechanisms drive the acquisition of new somatic mutations? To address these questions, I will use cutting-edge duplex single-nucleus whole genome sequencing to quantify the burden of somatic mutations in neuronal cell types in NF compared to age-matched controls and use the well-established method of unbiased non-negative matrix factorization to identify specific mechanisms driving mutagenesis.

项目概要 1 型神经纤维瘤病 (NF) 是一种常染色体显性癌症易感综合征，其特征是肿瘤遍布中枢和周围神经系统。除肿瘤外，约 80% 的 NF 患者还存在神经功能缺陷，包括记忆、注意力、知觉和执行功能受损。先前的工作已经确定了体细胞突变（仅存在于细胞亚群中的 DNA 合子后变化）对于 NF 肿瘤形成的重要性。尽管体细胞突变在 NF 发病机制中至关重要，并且对驱动肿瘤形成的特定突变进行了深入研究，但体细胞突变的整体动态仍知之甚少。与未受影响的个体相比，患有 NF 的个体是否具有更高的体细胞突变负担？神经元中罕见的体细胞突变是否会导致 NF 的神经功能缺陷？哪些遗传机制驱动新体细胞突变的获得？为了解决这些问题，我将使用尖端的双链单核全基因组测序来量化 NF 中神经元细胞类型与年龄匹配对照相比的体细胞突变负担，并使用成熟的无偏非负矩阵方法因子分解以确定驱动诱变的特定机制。