Neurodevelopmental Loci

神经发育位点

• 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
• 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

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。 DGAP受试者显示了高比例（〜70％） 神经发育障碍（NDD），包括自闭症谱系障碍（ASD），智力障碍（ID） 以及其他人，DGAP识别均衡染色体异常破坏基因的策略 （BCA）将继续成为人类基因的其他方法的主要来源 杂合灭活对NDD有很大贡献。在DGAP功能中鉴定的许多NDD基因 染色质调节并有助于多种NDD表型，表明ASD，ID之间的共享途径 和成人行为障碍。不同基因的强效应突变也会导致类似的表型， 暗示触发共同的神经发育途径。这些事实表明是公正的， 使用全球分子读出数据驱动的遗传策略将识别基因中的共同扰动 表达网络是灭活不同NDD基因的近端效应。通常是同一个DGAP主题 还显示非神经元表型，表明发育途径之间的潜在重叠 不同的器官系统，其中许多将是项目2的重点。使用项目1中确定的基因 在协调和行政核心（CAC）中确定的受试者将测试假设 通过创建靶向杂合突变（与项目密切协调）来收敛的NDD途径 1和2，特别是对于神经系统和周围异常的病例），并比较它们的作用 在等源性人诱导的多能干细胞（IPSC）中的基因表达网络上 神经元。在NDD中破坏的网络将允许分组不同的突变基因（以及受试者 将它们寄给他们）根据他们的共同后果并允许研究有效地部署 DGAP的遗传和细胞资源社区通过靶向最大产生的途径 适用的治疗干预措施。我们将进一步测试所有DGAP案例的基本假设，以 BCA和截短突变仅限于断点中断的基因，由于额外 核结构变化的距离（顺式或反式）对基因调节的影响 由BCA。最后，对于选定的基因，与项目1和2密切协调，我们将比较 人类受试者和斑马鱼模型中与细胞表型的基因型 - 表型关系，两者都 分子和功能，为将来的详细机制和可能的研究提供牢固的基础 干预措施。总体而言，我们公正的，数据驱动的遗传策略将确定基因网络的变化 对于不同基因的突变，可能揭示了失调导致NDD和的关键途径 允许根据共同的共同机制对受试者进行分类。等源性突变体 我们为研究社区提供的IPSC（单个基因敲除和不截断的等位基因系列） 将有助于进一步研究这些机制，发展和测试理性药物 干预措施。