Cell-type-specific NRXN1alpha alternative splicing changes in psychiatric disease

精神疾病中细胞类型特异性 NRXN1alpha 选择性剪接变化

基本信息

批准号：
10619023
负责人：
Kristen Jennifer Brennand
金额：
$ 74.11万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-18 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10619023
关键词：
3-Dimensional Adult Affect Affinity Age of Onset Alleles Alternative Splicing American Autopsy Behavioral Binding Bipolar Disorder Brain Cell Communication Cell model Clinical Complex Data Development Diagnosis Diagnostic Dominant-Negative Mutation Electrophysiology (science)Equilibrium Exhibits Failure Genes Genetic Genomics Genotype Glutamates Goals Heterozygote Human Impairment Induced pluripotent stem cell derived neurons Length Ligands Link Mental disorders Mus Mutation Neurodevelopmental Disorder Neurons Organoids Patients Penetrance Physiological Population Prognosis Prosencephalon Protein Isoforms Psychoses RNA Splicing Research Research Personnel Schizophrenia Severities Site Specific qualifier value Synapses Testing Tissues Work autism spectrum disorder cell type clinical predictors excitatory neuron fetal improved in vivo induced pluripotent stem cell inhibitory neuron mouse model multi-electrode arrays mutant neural circuit neuropsychiatric disorder neurotransmitter release novel novel therapeutic intervention overexpression postsynaptic postsynaptic neurons predict clinical outcome presynaptic presynaptic neurons recruit single cell analysis single-cell RNA sequencing standard care stem cell model synaptic function synaptogenesis

项目摘要

PROJECT SUMMARY Schizophrenia, bipolar disorder and autism are common and debilitating neurodevelopmental disorders that together affect more than 5 million Americans. Despite more than fifty years of research, no cures exist and the standard of treatment remains unsatisfactory. Heterozygous mutations of neurexin-1 (NRXN1) have been repeatedly associated with schizophrenia (SZ) and autism spectrum disorder (ASD). The clinical presentations of NRXN1+/- mutations (including diagnosis, severity, prognosis and age-of-onset) in affected patients are diverse and the genetic mechanism affecting the penetrance of these mutations remains unknown. Moreover, mouse models do not permit researchers to study how and why some NRXN1+/- deletions have more deleterious effects in patients. Our objective is to resolve how NRXN1+/- deletions perturb the NRXN1 isoform repertoire and impact neuronal maturation and synaptic function. Our preliminary data defined the NRXN1 alternative splice repertoire in control fetal and adult cortical tissue, and compared this to human induced pluripotent stem cell (hiPSC)-derived neurons from NRXN1+/- cases and controls. Here, we propose to evaluate the effect of experimental manipulation of the NRXN1 isoform repertoire in both control and NRXN1+/- patient-derived excitatory and inhibitory neurons. Ultimately, we hope to directly correlate genomic and functional deficits across increasingly refined populations of NRXN1+/- patient-derived neurons.

项目概要精神分裂症、双相情感障碍和自闭症是常见且使人衰弱的神经发育障碍，共同影响超过 500 万美国人。尽管经过五十多年的研究，仍然没有治愈方法，而且治疗水平仍不能令人满意。 neurexin-1 (NRXN1) 杂合突变反复与精神分裂症（SZ）和自闭症谱系障碍（ASD）相关。临床表现受影响患者的 NRXN1+/- 突变（包括诊断、严重程度、预后和发病年龄）影响这些突变外显率的遗传机制仍然未知。而且，小鼠模型不允许研究人员研究某些 NRXN1+/- 缺失如何以及为何具有更多功能对患者产生有害影响。我们的目标是解决 NRXN1+/- 缺失如何扰乱 NRXN1 同工型曲目并影响神经元成熟和突触功能。我们的初步数据定义了 NRXN1 对照胎儿和成人皮质组织中的替代剪接库，并将其与人类诱导的进行比较来自 NRXN1+/- 病例和对照的多能干细胞 (hiPSC) 衍生神经元。在此，我们建议评估对照和 NRXN1+/- 中 NRXN1 亚型库的实验操作效果患者来源的兴奋性和抑制性神经元。最终，我们希望将基因组和日益精细的 NRXN1+/- 患者源性神经元群体的功能缺陷。