Neurodevelopmental Loci

神经发育位点

基本信息

批准号：
8854517
负责人：
JAMES F GUSELLA
金额：
$ 38.72万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8854517
关键词：
Adult Anatomy Animals Architecture Behavior Disorders Behavioral Biological Assay Cell Culture Techniques Cell Line Cell model Cells Cellular Assay Chromatin Chromosomal Rearrangement Chromosome abnormality Chromosomes Classification Clinical Clustered Regularly Interspaced Short Palindromic Repeats Code Communities Complement Complex Critical Pathways DNA Methylation Data Development Developmental Gene Developmental Process Disease Distant Equilibrium Event Future Gene Expression Gene Expression Regulation Gene Mutation Gene Silencing Gene Targeting Genes Genetic Genome Genotype Grouping Human Individual Intellectual functioning disability Intervention Investigation Knock-out Knowledge Lead Location Modeling Molecular Molecular Conformation Mutate Mutation Neurodevelopmental Disorder Neurologic Neuronal Differentiation Neurons Nuclear Pathway Analysis Pathway interactions Patients Pattern Peripheral Pharmacologic Substance Phenotype Preclinical Drug Evaluation Proteins RNA Sequences Reading Regulation Research Resources Series Source Staging System Technology Testing Therapeutic Intervention Tissue-Specific Gene Expression Transcriptional Regulation Untranslated RNA Zebrafish abstracting autism spectrum disorder base body system chromatin modification clinical phenotype disability dosage gene discovery gene function human subject induced pluripotent stem cell innovation interest molecular phenotype mutant transcriptome sequencing variant of unknown significance

项目摘要

PROJECT 3 ABSTRACT/RESEARCH SUMMARY. A high proportion (~70%) of DGAP subjects display neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability (ID) and others, so DGAP's strategy of identifying the gene(s) disrupted by balanced chromosome abnormalities (BCAs) will continue to be a major source, complementary to other approaches, of human genes whose heterozygous inactivation contributes strongly to NDD. Many NDD genes identified in DGAP function in chromatin regulation and contribute to multiple NDD phenotypes, indicating shared pathways between ASD, ID and adult behavioral disorders. Strong effect mutations in different genes can also lead to a similar phenotype, suggesting the triggering of shared neurodevelopmental pathways. These facts suggest that an unbiased, data-driven genetic strategy using global molecular read-outs will identify shared perturbations in gene expression networks as proximal effects of inactivating different NDD genes. Often the same DGAP subjects also display non-neuronal phenotypes, indicating potential overlaps between developmental pathways in different organ systems, many of which will be the focus of Project 2. Using genes identified in Project 1 from subjects ascertained in the Coordinating and Administrative Core (CAC), Project 3 will test the hypothesis of convergent NDD pathways by creating targeted heterozygous mutations (in close coordination with Projects 1 and 2, especially for cases with both neurological and peripheral abnormalities) and comparing their effects on networks of gene expression in isogenic human induced pluripotent stem cells (iPSC) and differentiating neurons. Networks disrupted in NDDs will allow grouping of different mutated genes (and the subjects who harbor them) based upon their shared consequences and permit efficient deployment by the research community of the genetic and cellular resources of DGAP by targeting the pathways most likely to yield broadly applicable therapeutic interventions. We will further test a basic hypothesis germane to all DGAP cases, that BCAs and truncating mutations limited to the breakpoint-disrupted gene are not identical due to additional effects on gene regulation at a distance (in cis or trans) from changes in the nuclear architecture occasioned by the BCA. Finally, for selected genes, in close coordination with Projects 1 and 2, we will compare genotype-phenotype relationships in human subjects and zebrafish models to cellular phenotypes, both molecular and functional, to provide a firm basis for future studies of detailed mechanisms and possible interventions. Overall, our unbiased, data-driven, genetic strategy will identify alterations of gene networks due to mutations in different genes, potentially revealing critical pathways whose dysregulation leads to NDD and allowing classification of subjects based upon common shared mechanisms. The isogenic mutant human iPSCs (individual gene knock-out and non-truncating allelic series) that we provide for the research community will facilitate further investigation of these mechanisms and development and testing of rational pharmaceutical interventions.

项目 3 摘要/研究摘要。高比例 (~70%) 的 DGAP 科目显示神经发育障碍 (NDD)，包括自闭症谱系障碍 (ASD)、智力障碍 (ID) 等，因此 DGAP 的策略是识别因平衡染色体异常而破坏的基因（BCA）将继续成为人类基因的主要来源，与其他方法相辅相成。杂合失活对 NDD 有很大影响。许多 NDD 基因在 DGAP 功能中被鉴定染色质调节并导致多种 NDD 表型，表明 ASD、ID 之间存在共享途径和成人行为障碍。不同基因的强效应突变也可以导致相似的表型，表明触发了共享的神经发育途径。这些事实表明，公正、使用全局分子读数的数据驱动遗传策略将识别基因中的共同扰动表达网络作为不同 NDD 基因失活的近端效应。通常是相同的 DGAP 科目还表现出非神经元表型，表明发育途径之间存在潜在重叠不同的器官系统，其中许多将成为项目 2 的重点。使用项目 1 中鉴定的基因协调和管理核心 (CAC) 中确定的科目，项目 3 将检验假设通过创建有针对性的杂合突变（与项目密切协调） 1和2，特别是对于同时存在神经系统和外周异常的病例）并比较它们的效果等基因人类诱导多能干细胞（iPSC）基因表达网络的研究和分化神经元。 NDD 中被破坏的网络将允许对不同的突变基因进行分组（以及庇护它们）基于它们共同的后果，并允许研究有效部署通过针对最有可能广泛产生的途径，建立 DGAP 遗传和细胞资源的社区适用的治疗干预措施。我们将进一步检验与所有 DGAP 案例密切相关的基本假设，即 BCA 和仅限于断点破坏基因的截短突变并不相同，因为额外的核结构变化对远距离（顺式或反式）基因调控的影响由建设局。最后，对于选定的基因，与项目 1 和 2 密切配合，我们将比较人类受试者和斑马鱼模型与细胞表型的基因型-表型关系分子和功能，为未来详细机制和可能的研究提供坚实的基础干预措施。总体而言，我们公正的、数据驱动的遗传策略将识别由于基因网络的改变不同基因的突变，可能揭示其失调导致 NDD 和允许根据共同的共享机制对主题进行分类。同基因突变人类我们为研究界提供的 iPSC（个体基因敲除和非截断等位基因系列）将有助于进一步研究这些机制以及合理药物的开发和测试干预措施。