Using integrated omics to identify dysfunctional genetic mechanisms influencing schizophrenia and sleep disturbances

使用整合组学来识别影响精神分裂症和睡眠障碍的功能失调的遗传机制

• 批准号: 10770880
• 负责人: Steven Allan Soper
• 金额: $ 25.5万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2024-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10770880
• 关键词: Biochemical Genetics; Biochemical Pathway; Brain; Brain region; Caring; Communities; Data; Diagnosis; Disease; Drug Targeting; Early Diagnosis; Early Intervention; Female; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Genomics; Goals; Human; Individual; Investigation; Kansas; Knowledge; Medical; Medical center; Mental Health; Multiomic Data; Outcome; Patients; Pharmacogenetics; Proteins; Proteome; Race; Reporting; Research Personnel; Resources; Risk; Schizophrenia; Severities; Sleep; Sleep Disorders; Sleep disturbances; Sleeplessness; Specimen; Symptoms; Universities; Variant; Work; improved; male; neurodevelopment; pleiotropism; precision medicine; risk prediction; sample collection; sleep behavior; sleep regulation; small molecule; transcriptome

The proposed work aims to decipher genetic factors dysregulated in the brains of individuals with schizophrenia with pleiotropic effects influencing sleep issues. The goals are to inform genomic driven medical care for improved treatment of sleep problems, which are among the most common co-occurring conditions in these patients. Sleep disruptions are associated with more severe schizophrenia-related symptoms. Healthy sleep is important for neurodevelopment, indicating that managing sleep disturbances may have significant impacts on reducing severity of schizophrenia symptoms and improving long-term outcomes. Characterizing pleiotropic genetic effects using multiomics data holds promise for informing precision medicine approaches to treatment of sleep problems in these individuals. Investigators at the University of Kansas Medical Center have whole brain specimens from human donors diagnosed with schizophrenia and confirmed controls. This brain bank reflects a diverse collection of specimens from males and females with different reported race. This project will generate multi-omics data from sleep-wake regulating brain regions in these specimens and identify genetic variation impacting function of pleiotropic genes and proteins evidenced to increase risk for both schizophrenia and insomnia-related symptoms. Variants with evidence for pharmacogenetic and regulatory effects on genes encoding drug targets will be evaluated. Genetic risk scores calculated from sequence data that are useful to predicting risk and aiding in early detection and intervention will be functionally validated. In addition, this project will comprehensively characterize gene and protein coexpression connecting two important brain regions known to regulate human sleep behaviors. Combining evidence from the genome, transcriptome and proteome will allow for discerning the biochemical pathways and genetic mechanisms dysregulated in sleep-wake regulating brain regions from these patients and help identify proteins that can be targeted by small molecule compounds to treat sleep problems more effectively. This work should also provide knowledge of how convergent mechanisms influence risk for multiple disorders in the same individual. The approaches developed and data generated in this project will provide a rich resource that will be shared with the larger scientific community allowing for investigations of the sleep regulation network in a diverse representation of individuals with mental health conditions.

这项拟议的工作旨在破译患有脑部疾病的人大脑中失调的遗传因素。 具有多效性影响睡眠问题的精神分裂症。我们的目标是让基因组驱动 改善睡眠问题治疗的医疗护理，睡眠问题是最常见的共生问题之一 这些患者的病情。睡眠障碍与更严重的精神分裂症相关 症状。健康的睡眠对神经发育很重要，这表明管理睡眠障碍 可能对减轻精神分裂症症状的严重程度和改善长期生活质量有显著影响 结果。利用多组学数据表征多效性遗传效应有望为 精准医学方法治疗这些人的睡眠问题。该中心的调查人员 堪萨斯大学医学中心有来自人类捐赠者的全脑样本被诊断为 精神分裂症和确认的对照。这个脑库反映了来自 报告种族不同的男性和女性。该项目将从以下方面生成多组学数据 这些标本中睡眠-觉醒调节脑区并鉴定影响功能的遗传变异 多效性基因和蛋白质被证明增加了精神分裂症和失眠相关的风险 症状。对编码药物的基因具有药物遗传和调控作用的证据的变体 将对目标进行评估。根据序列数据计算的对预测有用的遗传风险分数 风险和对早期检测和干预的帮助将在功能上得到验证。此外，该项目还将 连接两个重要脑区的基因和蛋白质共表达的综合表征 已知可以调节人类的睡眠行为。结合来自基因组、转录组和 蛋白质组学将有助于辨别失控的生物化学途径和遗传机制。 这些患者的睡眠-觉醒调节脑区，并帮助识别可以靶向的蛋白质 小分子化合物可以更有效地治疗睡眠问题。这项工作还应该提供 了解汇聚机制如何影响同一个体中多种疾病的风险。 在这个项目中开发的方法和生成的数据将提供丰富的资源，将 与更大的科学界共享，允许在 有精神健康状况的个人的不同代表。