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Origins of Brain Somatic Mosaicism in Developmental Brain Disease

发育性脑疾病中脑体细胞嵌合的起源

基本信息

批准号：
10466904
负责人：
JOSEPH G GLEESON
金额：
$ 31.25万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2021-08-10 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10466904
关键词：
Adult Algorithms Alleles Anatomy Animal Model Astrocytes Autopsy Bar Codes Behavior Blood Brain Brain Diseases Cadaver Candidate Disease Gene Cell Lineage Cell Size Cell division Cells Chemicals Childhood Clinical Complex Cortical Dysplasia DNA DNA Methylation DNA Repair DNA Sequence Alteration Data Databases Detection Development Developmental Process Disease Dysplasia Electroencephalography Electroporation Embryo Embryonic Development Evaluation Excision Exposure to FRAP1 gene Freezing Frequencies Functional disorder Funding Genetic Genetic Variation Genomics Genotype Goals Growth Human Individual Intractable Epilepsy Investments Knowledge Life Maps Metabolic stress Methods Microglia Minority Modeling Mosaicism Mus Mutation Neurons Nuclear Oligodendroglia Operative Surgical Procedures Organism Outcome Pathogenicity Pathway interactions Patients Pattern Pharmacology Phenotype Play Predisposition Recording of previous events Resected Role Sampling Shapes Signal Transduction Somatic Cell Somatic Mutation Sorting - Cell Movement Synapses Testing Tissues Variant Work brain cell brain circuitry cell type clinically significant cohort daughter cell deep sequencing demethylation disability gene function genome sequencing genomic variation human model in utero interest loss of function mTOR Inhibitor migration mouse model mutant neocortical neurogenesis neuron development neuronal circuitry neuropsychiatric disorder neuropsychiatry novel recruit relating to nervous system resilience response success synaptic function

项目摘要

Abstract Brain somatic mosaicism (BSM) refers to the accumulation of mutations within any of the billions of cells in the human brain, which can occur from embryogenesis through adulthood. The extent, impact and mechanisms of BSM on brain disease remain poorly understood. Prior work from the Brain Somatic Mosaicism Network (BSMN), on which the PI served, made critical breakthroughs in reliability of mosaicism detection, but also raised new questions, including the degree to which BSM exists in the healthy brain, and the mechanisms by which BSM mutations explain disease. Focal cortical dysplasia (FCD) is associated with substantial neuropsychiatric disability, and is the most common cause of intractable epilepsy in childhood. Neuropsychiatric features are seen in 15-59% of patients 5-7, and neuropathologically shows disrupted neurogenesis, migration, differentiation, and altered neural excitability. We and others previously identified mosaic mutations in the mTOR pathway in a minority of FCD cases, but most cases remain unsolved, and fundamental mechanisms are lacking. We hypothesize that: 1] FCD mutations are similar to neutral somatic mutations in their patterns and distributions, dictated by developmental processes, but differ in their functional effect. 2] BSM patterns, allelic fractions (AFs) and allele sharing between cells can reconstruct cellular lineages and migratory histories. 3] Study of FCD resected tissue can uncover novel causes of disease that would not be tolerated if present in every cell. 4] BSM modeling in mouse can unravel disrupted signaling networks of complex mosaic mutations. Our preliminary data shows: 1] From a post-mortem control cadaver, we validated 259 somatic variants using 300X genome sequencing, and started to use these variants as ‘barcodes’ to reconstruct lineage histories. 2] Deep sequencing from 314 FCD patient brain resections identified 12 new candidate genes, highlighting signaling and synaptic dysfunction, and a novel ‘two-hit’ disease mechanisms. 3] We established in utero mouse electroporation models to assess putative FCD variants as gain or loss of function, and to assess effects of ‘single-hit’ and ‘two-hit’ mutations. We propose three aims: 1] From control cadavers, we will reconstruct cell lineage across anatomical domains using BSM as barcodes. 2] With this lineage information, we will study the origins of BSM mutations in FCD, by recruiting new patients, performing both targeted and unbiased sequencing, and identifying novel causes. 3] We will functionally validate putative deleterious alleles in animal models for both ‘single-hit’ and ‘two-hit’ causes. The goal is to achieve a mechanistic understanding of the extent of BSM in control individuals, to reconstruct neural lineages and to identify novel mechanisms in developmental brain disease.

摘要