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：
10407104
负责人：
Kristen Jennifer Brennand
金额：
$ 78.99万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407104
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 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 Synapses Testing Tissues Work autism spectrum disorder case control 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.

项目摘要精神分裂症，躁郁症和自闭症是常见的，使神经发育障碍使人衰弱共同影响超过500万美国人。尽管研究了五十多年，但尚无治疗方法治疗标准仍然不令人满意。 Neurexin-1（NRXN1）的杂合突变已经反复与精神分裂症（SZ）和自闭症谱系障碍（ASD）相关。临床演示受影响患者的NRXN1 +/-突变（包括诊断，严重程度，预后和发病年龄）是多样化和影响这些突变渗透率的遗传机制仍然未知。而且，鼠标模型不允许研究人员研究某些NRXN1 +/-缺失的方式以及为什么患者有害影响。我们的目标是解决NRXN1 +/-删除如何扰动NRXN1同工型曲目和影响神经元的成熟和突触功能。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曲目，并将其与人类诱导的来自NRXN1 +/-病例和对照组的多能干细胞（HIPSC）衍生的神经元。在这里，我们建议评估NRXN1同工型库在对照和NRXN1 +/-中的实验操作的效果患者衍生的兴奋性和抑制性神经元。最终，我们希望直接关联基因组和 NRXN1 +/-患者衍生的神经元种群越来越精致的人群的功能缺陷。