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：
10462568
负责人：
Kristen Jennifer Brennand
金额：
$ 80.97万
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/10462568
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 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 base 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.

项目概要精神分裂症 (SZ)、双向情感障碍 (BD) 和自闭症谱系障碍 (ASD) 很常见且令人衰弱神经发育障碍共同影响了超过 500 万美国人。尽管五十多年根据研究，尚无治愈方法，治疗标准仍不令人满意。替代品监管失调人类大脑中的剪接与 SZ 有关。在具有关键大脑功能的基因中，许多基因具有大量的外显子，导致复杂的剪接模式在神经元亚型之间可能有所不同；然而，大多数这些复杂基因的亚型库尚未在细胞类型特异性中得到解决。方式。长读长测序的最新进展为解决这一问题提供了前所未有的机会复杂的选择性剪接。因此，为了更好地了解可变剪接变化的临床影响精神疾病，评估亚型库如何影响神经元成熟和突触至关重要以细胞类型特定的方式发挥作用。在这里，我们建议对使用单细胞长读长测序研究 SZ 相关基因的人类亚型库的复杂性基于方法，并研究遗传变异如何影响选择性剪接并影响神经元以亚型特定方式的成熟和突触功能。该项目将提供全面的 SZ 基因的细胞特异性完整亚型库目录，将广泛促进 SZ 研究。它还将加深对遗传变异和选择性剪接如何影响 SZ 的理解，帮助更好地预测临床结果并确定新的治疗干预措施。本研究中使用的单细胞方法项目一般适用于研究其他精神障碍，如 BD 和 ASD。