A Gene-Network Discovery Approach to Structural Brain Disorders

结构性脑疾病的基因网络发现方法

基本信息

批准号：
10734863
负责人：
Kaya Bilguvar
金额：
$ 68.49万
依托单位：
YALE UNIVERSITY
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：
2023-09-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734863
关键词：
3-Dimensional Address Adult Affect Anterior Apoptosis Biology Brain Brain Diseases CASP2 gene Candidate Disease Gene Cell Cycle Arrest Cell Line Cell physiology Centrosome Cerebral cortex Cerebrum Cortical Malformation Critical Thinking DNA Damage DNA sequencing Data Data Set Development Developmental Delay Disorders Disease Embryo Etiology Family Future Genes Genetic Genetic Complementation Test Genetic Heterogeneity Genomics Genotype Health Heterogeneity Human Impairment In Vitro Induction of Apoptosis Intellectual functioning disability Intervention Investigation Knock-in Mediating Mendelian disorder Methods Modeling Molecular Multiprotein Complexes Mus Mutant Strains Mice Mutation Neocortex Network-based Neuroglia Neuronal Differentiation Neurons Organelles Organoids Pathogenicity Pathology Pathway Analysis Pathway interactions Patients Phenotype Pilot Projects Polynomial Models Process Proliferating RNA Splicing Reporting Role Sampling Seizures Site System Thinness Validation Variant Work brain malformation candidate identification causal variant cell type cohort consanguineous family developmental disease exome sequencing fetal gene discovery gene network genetic disorder diagnosis genome editing human stem cells in vivo indexing induced pluripotent stem cell insight keratinocyte kindred lissencephaly malformation member migration mouse model mutant neocortical nerve stem cell neural neurodevelopment neurogenesis neurogenetics next generation next generation sequencing novel novel strategies pachygyria protein complex response segregation single-cell RNA sequencing stem cell model stem cells virulence gene

项目摘要

Project Summary/Abstract Lissencephaly is a rare developmental disorder characterized by absence or simplification of brain convolutions. With no available cure, it leads to significant health burden of developmental delay, intellectual disability, and seizures. While introduction of next-generation DNA sequencing offered unprecedented opportunities for gene discovery in human disorders, leading to the identification of an array of lissencephaly-associated genes, approximately a fifth of patients with lissencephaly still lack genetic diagnosis. Gene discovery in Mendelian disorders is hampered by locus and phenotypic heterogeneity and thus, a systems-level analysis complemented with mechanistic characterization of candidate variants is warranted. In the past decade and a half, we have identified and functionally characterized multiple genes whose disruption is associated with malformations of the human cerebral cortex. We propose to utilize patient- derived stem cell and embryonic mouse models to characterize the role of the PIDDosome protein complex in human brain development and understand how its malfunction can cause lissencephaly. We also propose to perform gene- burden and co-expression analyses to inform characterization of novel genes and pathways involved in lissencephaly through modeling in organoids. We will use patient and control keratinocytes to generate induced pluripotent stem cells and 2D and 3D neural derivatives to define the molecular and cellular consequences of PIDD1 mutations, accompanied by in vivo mouse models of PIDD1 loss during neurodevelopment. We will perform gene network-based analysis of human brain development and mutation burden analysis at the gene and pathway level of 120 lissencephaly patients with available whole-exome sequencing data to identify and prioritize novel causal genes for lissencephaly. Our multi- faceted approach is expected to reveal shared molecular pathways and affected cell types that are perturbed during human fetal neurodevelopment leading to the onset of lissencephaly in a genetically heterogenous background, also providing an analytical framework for variant prioritization in large-scale genomic investigation of human disorders.

项目摘要/摘要 Lissphaly是一种罕见的发育障碍，其特征是缺乏或简化大脑卷积。没有可用的治疗方法，会导致发育延迟，智力残疾和癫痫发作的重大健康负担。尽管下一代DNA测序的引入为人类的基因发现提供了前所未有的机会疾病，导致鉴定与Lissencephaly相关的基因阵列，大约五分之一的患者脑脑仍然缺乏遗传诊断。 Mendelian疾病中的基因发现受到基因座和表型异质性，因此，系统级分析与机械表征相辅相成保证候选变体。在过去的十年中，我们已经确定并在功能上表征了多个破坏与人脑皮质的畸形有关的基因。我们建议利用患者 - 衍生的干细胞和胚胎小鼠模型，以表征人类蛋白质复合物在人类中的作用大脑发育并了解其故障如何引起脑脑。我们还建议执行基因负担和共表达分析，以告知涉及Lissencephaly的新基因和途径的表征通过在器官中进行建模。我们将使用患者并控制角质形成细胞产生诱导的多能干细胞以及2D和3D神经衍生物，以定义PIDD1突变的分子和细胞后果通过神经发育过程中PIDD1损失的体内小鼠模型。我们将对基因网络进行基于基因网络的分析人脑发育和突变负担分析在120名Lissencephaly患者的基因和途径水平上具有可用的全外观测序数据，以识别和优先考虑新的因果基因。我们的多有望在人类胎儿神经发育导致遗传异源背景中的Lissencephaly发作，也是在人类疾病的大规模基因组研究中，提供了一个分析框架，以进行变异的优先级。