Schizophrenia biomarkers discerned by cellular networks in DiGeorge syndrome

迪乔治综合征细胞网络识别的精神分裂症生物标志物

• 批准号: 7590731
• 负责人: BRADLEY D PEARCE
• 金额: $ 23.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590731
• 关键词: 21 year old; 22q11; 22q11 Deletion Syndrome; 22q11.2; Adolescent; Adult; Affect; Age; B-Lymphocytes; Binding; Bioinformatics; Biological Markers; Blood; Blood Cells; Brain; Cell physiology; Cells; Cellular Stress; Chromosomes; Chronic Schizophrenia; Communication; Complex; Computer software; Confounding Factors (Epidemiology); Control Groups; Data; Databases; Defect; DiGeorge Syndrome; Diagnosis; Diagnostic and Statistical Manual; Disease; Disease susceptibility; Environmental Risk Factor; Etiology; Fibroblasts; Gene Expression; Gene Expression Profile; Gene Proteins; Genes; Genetic; Goals; Hereditary Disease; Hypoxia; Individual; Marshal; Measures; Mental disorders; Messenger RNA; Molecular; Molecular Profiling; Nature; Oxygen; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Pattern; Peripheral; Placenta; Population Study; Proteins; Psychometrics; Psychopathology; Regression Analysis; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Schizophrenia; Schizotypal Personality Disorder; Shprintzen syndrome; Staging; Susceptibility Gene; System; Tissues; Transcript; Variant; deprivation; design; disorder subtype; fetal blood; fetus hypoxia; genome-wide; improved; microdeletion; novel; prepulse inhibition; public health relevance; response; therapeutic target; tool

DESCRIPTION (provided by applicant): Any hypothesis of schizophrenia etiology should ultimately consider its genetic diatheses, neurodevelopmental antecedents (i.e. fetal hypoxia), and environmental components. Schizophrenia is a heterogeneous disease, and hence there are advantages to studying patients with related disorders (e.g. schizotypal personality disorder), or subtypes of the disorder. DiGeorge syndrome is a genetic disorder characterized by delimited microdeletions in chromosome 22q11.2 and a high rate of schizophrenia. Because one copy of the 22q11 deleted region remains in DiGeorge syndrome, we hypothesize that some cellular and molecular pathways that utilize proteins encoded by 22q11.2 will be disrupted while others may remain relatively intact. The goal of this application is to use peripherally-accessible tissue from patients with this genetically- defined risk for schizophrenia in order to elucidate molecular pathways that have general applicability to other schizophrenia spectrum disorders. In Aim 1 we plan to profile the expression of 36 definitive genes in the known deleted region of DiGeorge syndrome (adolescent) patients and a control group without this deletion or mental illness. By studying populations at the premorbid stage, some of the confounding variables that attend chronic schizophrenia can be overcome. Furthermore, we plan to determine whether the genes (and/or proteins) that we find to have abnormal expression patterns in the DiGeorge syndrome patients are also affected in schizophrenic patients who do not have 22q11 deletions. Gene expression data in DiGeorge syndrome patients and idiopathic schizophrenia patients will be correlated with psychometric assessment scores. In Aim 2 we will examine the impact of hypoxia on these pathways using fibroblasts from DiGeorge syndrome patients and controls. Molecular pathways will be discerned in relation to other putative schizophrenia susceptibility genes with the aid of bioinformatics software that identifies pathways and inter-relationships at the level of genes, proteins, cells, and tissues. We anticipate these studies will open new opportunities for peripheral biomarkers that can elucidate schizophrenia pathogenesis, and may also reveal therapeutic targets that were never previously considered. PUBLIC HEALTH RELEVANCE; Despite progress on many fronts, the causes of schizophrenia are not known. If researchers can discover the underlying cellular defects in schizophrenia, novel and improved treatments can be designed. This study examines such cellular abnormalities in schizophrenia and a "variant" of the disease called DiGeorge syndrome.

描述（由申请人提供）：任何精神分裂症病因学的假设最终都应考虑其遗传素质、神经发育前因（即胎儿缺氧）和环境因素。精神分裂症是一种异质性疾病，因此研究具有相关障碍（例如，典型人格障碍）或该障碍亚型的患者是有优势的。DiGeorge综合征是一种遗传性疾病，其特征是染色体22q11.2的限定性微缺失和精神分裂症的高发病率。由于22 q11缺失区的一个拷贝仍然存在于DiGeorge综合征中，我们假设利用22q11.2编码的蛋白质的一些细胞和分子途径将被破坏，而其他途径可能保持相对完整。本申请的目的是使用来自具有这种遗传上确定的精神分裂症风险的患者的外周可及组织，以阐明对其他精神分裂症谱系障碍具有普遍适用性的分子途径。在目标1中，我们计划在已知的迪乔治综合征（青少年）患者和对照组没有这种缺失或精神疾病的缺失区域中分析36个决定性基因的表达。通过研究发病前阶段的人群，可以克服慢性精神分裂症的一些混杂变量。此外，我们计划确定我们在DiGeorge综合征患者中发现的异常表达模式的基因（和/或蛋白质）是否也会影响没有22 q11缺失的精神分裂症患者。DiGeorge综合征患者和特发性精神分裂症患者的基因表达数据将与心理测量评估评分相关。在目标2中，我们将使用DiGeorge综合征患者和对照组的成纤维细胞研究缺氧对这些通路的影响。分子途径将与其他推定的精神分裂症易感基因的生物信息学软件的帮助下，确定在基因，蛋白质，细胞和组织的水平上的途径和相互关系。我们预计这些研究将为阐明精神分裂症发病机制的外周生物标志物开辟新的机会，也可能揭示以前从未考虑过的治疗靶点。与公共卫生的关系：尽管在许多方面取得了进展，但精神分裂症的病因尚不清楚。如果研究人员能够发现精神分裂症中潜在的细胞缺陷，就可以设计出新的和改进的治疗方法。这项研究检查了精神分裂症和一种称为迪乔治综合征的疾病的“变体”中的细胞异常。