Schizophrenia Biomarkers: Blood vs Brain Gene Expression

精神分裂症生物标志物：血液与大脑基因表达

• 批准号: 7140257
• 负责人: MING T. TSUANG
• 金额: $ 12.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-27 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140257
• 关键词: antipsychotic agents; behavioral genetics; bioinformatics; biomarker; bipolar depression; blood tests; brain; clinical research; diagnosis design /evaluation; diagnostic tests; early diagnosis; gene expression; gene expression profiling; human subject; human tissue; lymphocyte; mental disorder diagnosis; messenger RNA; microarray technology; nucleic acid quantitation /detection; patient oriented research; pharmacogenetics; postmortem; psychopharmacology; schizophrenia; tissue /cell culture

DESCRIPTION (provided by applicant): The diagnosis of schizophrenia presently relies on essentially the same methods of clinical interviewing, symptom identification, and application of diagnostic criteria that have been in use for nearly 25 years. Given the considerable genetic contribution toward the etiology of schizophrenia, a biologically based set of diagnostic markers may be more efficient for validating the diagnosis and its subtypes, and for improving diagnostic sensitivity and specificity. Moreover, if diagnostic markers can be identified in peripheral blood rather than in postmortem brain tissue, the promise of early identification and improved treatment might be realized. As a first step toward establishing such biologically based markers, the main objective of this project is to identify and validate highly reliable and specific patterns of gene expression in peripheral blood cells that differentiate patients with schizophrenia from control subjects. We have generated pilot data identifying differences in gene expression profiles between patients with schizophrenia, patients with bipolar disorder, and control subjects; in the proposed project, novel applications of oligonucleotide microarrays and advanced statistical techniques will be used to extend and validate these preliminary findings. To accomplish this, we propose the following specific aims: 1) Quantify gene expression levels in peripheral lymphocytes from patients with schizophrenia and control subjects; 2) Quantify levels of gene expression induced by the application of typical and atypical antipsychotic medications to cultured lymphocytes obtained from control subjects, in order to rule out candidate biomarker genes that respond to medication but are not specific to the disease process; 3) Prioritize candidate genes for subsequent verification and validation as disease biomarkers using novel data-analytic and statistical methods that control the rate of inferential errors; 4) Verify the differential expression of top candidate genes in peripheral lymphocytes by more precise mRNA quantification techniques; and 5) Validate the differential expression of top candidate genes in postmortem brain tissue obtained from patients with schizophrenia and control subjects. Long-term goals (beyond this proposal) will be to replicate and extend our findings, test for other potential confounders of peripheral bloodbased gene expression profiling, and test for specificity vis-a-vis psychiatric comparison groups. Ultimately, biologically based diagnostic markers may substantially enhance the possibilities for early identification, intervention, and prevention, and also facilitate the identification of etiologic factors in the illness.

描述（由申请人提供）：精神分裂症的诊断目前依赖于临床访谈，症状识别和诊断标准的应用，这些方法已经使用了将近25年。鉴于对精神分裂症病因的遗传学贡献相当大，基于生物学的诊断标记物可能更有效地验证诊断及其亚型，以及提高诊断敏感性和特异性。此外，如果可以在外周血而不是在死后脑组织中鉴定诊断标记，则可以实现早期鉴定和改善治疗的希望。作为建立此类基于生物学的标记的第一步，该项目的主要目的是鉴定并验证外周血细胞中基因表达的高度可靠和特定模式，这些模式将精神分裂症患者与对照组分化。我们已经生成了试点数据，鉴定了精神分裂症患者，躁郁症和对照组患者之间基因表达谱的差异。在拟议的项目中，寡核苷酸微阵列和高级统计技术的新应用将用于扩展和验证这些初步发现。为此，我们提出了以下特定目的：1）量化精神分裂症患者和对照组患者的外周淋巴细胞中基因表达水平； 2）通过将典型和非典型抗精神病药物应用于从对照组受试者获得的培养的淋巴细胞中，量化基因表达水平，以排除对药物反应但对疾病过程不具体反应的候选生物标志物基因； 3）优先使用新型的数据分析和统计方法来控制候选基因，以随后的验证和验证为疾病生物标志物，以控制推论误差的速度； 4）通过更精确的mRNA定量技术来验证外周淋巴细胞中顶级候选基因的差异表达； 5）验证从精神分裂症患者和对照组患者获得的死后脑组织中顶级候选基因的差异表达。长期目标（超出此提案）将是复制和扩展我们的发现，测试其他潜在的基于血液的基因表达分析的混杂因素，并测试针对精神病学比较组的特异性。最终，基于生物学的诊断标记可能会大大提高早期鉴定，干预和预防的可能性，并促进疾病中病因学因素的识别。