Resolving complex alternative splicing of psychiatric disease genes using single-cell approaches

使用单细胞方法解决精神疾病基因的复杂选择性剪接

基本信息

批准号：
10630216
负责人：
Kristen Jennifer Brennand
金额：
$ 75.69万
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：
2021
资助国家：
美国
起止时间：
2021-08-05 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630216
关键词：
3-Dimensional Adult Affect Alternative Splicing American Autopsy Bipolar Disorder Brain Brain Diseases Catalogs Cell Communication Cell model Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Development Diagnostic Engineering Exhibits Exons Experimental Designs Failure Genes Genetic Variation Genetic study Genotype Glutamates Goals Human Impairment Induced pluripotent stem cell derived neurons Length Maps Mental disorders Neurodevelopmental Disorder Neurons Organoids Pattern Phenotype Physiological Prosencephalon Protein Isoforms Quantitative Trait Loci RNA Splicing Research Resolution Schizophrenia Synapses Technology Tissues Work autism spectrum disorder brain tissue cell type clinical predictors differential expression fetal improved induced pluripotent stem cell mind control mutant neural circuit neuropsychiatric disorder novel novel therapeutic intervention overexpression predict clinical outcome risk variant schizophrenia risk single cell sequencing standard care synaptic function targeted sequencing transcriptomics

项目摘要

PROJECT SUMMARY Schizophrenia (SZ), bipolar disorder (BD) and autism spectrum disorder (ASD) 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. Dysregulation of alternative splicing in the human brain has been implicated in SZ. Among genes with critical brain functions, many have a large number of exons, resulting in complex splicing patterns that can vary between neuronal subtypes; however, the isoform repertoires of most of these complex genes have not been resolved in a cell-type specific manner. Recent advances in long read sequencing have provided an unprecedented opportunity to resolve complex alternative splicing. Thus, to better understand the clinical impact of changes of alternative splicing in psychiatric diseases, it is critical to evaluate how isoform repertoire impact neuronal maturation and synaptic function in a cell-type specific manner. Here, we propose to catalog and functionally characterize the complexity of human isoform repertoires of SZ-associated genes using a single-cell long-read sequencing based approach, and to study how genetic variations influence alternative splicing and impact neuronal maturation and synaptic function in a subtype specific manner. This project will provide comprehensive catalogs of cell-specific full isoform repertoires of SZ genes that will broadly facilitate SZ research. It will also deepen the understanding of how genetic variations and alternative splicing contribute to SZ, help better predict the clinical outcome and identify novel therapeutic interventions. The single cell approach used in this project is generally applicable to study other mental disorders such as BD and ASD.

项目摘要精神分裂症（SZ），躁郁症（BD）和自闭症谱系障碍（ASD）是常见的，使人衰弱神经发育障碍共同影响超过500万美国人。尽管超过五十年在研究中，不存在治疗方法，并且治疗标准仍然不令人满意。替代方案的失调人脑中的剪接与SZ有关。在具有关键大脑功能的基因中，许多人具有大量外显子，导致复杂的剪接模式在神经元亚型之间变化；但是，这些复杂基因中大多数的同工型库尚未在细胞类型的特异性中解析方式。长期阅读测序的最新进展为解决方案提供了前所未有的机会复杂的替代剪接。因此，更好地了解替代剪接变化的临床影响精神病疾病，评估同工构曲目如何影响神经元成熟和突触是至关重要的以细胞类型的特定方式功能。在这里，我们提议分类并在功能上表征使用单细胞长读测序的SZ相关基因的人类同工型曲目的复杂性基于基于的方法，并研究遗传变异如何影响替代剪接和影响神经元以亚型特异性方式成熟和突触函数。该项目将提供全面 SZ基因的细胞特异性全同工型库的目录，这些基因将广泛促进SZ研究。它也会加深对遗传变异和替代剪接对SZ的贡献的理解，帮助更好预测临床结果并确定新的治疗干预措施。在此使用的单个单元方式项目通常适用于研究其他精神疾病，例如BD和ASD。