Transcriptome association with inflammation-related major depression

转录组与炎症相关重度抑郁症的关联

• 批准号: 8384387
• 负责人: FRANCIS E LOTRICH
• 金额: $ 15.56万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384387
• 关键词: Adult; Alleles; Amygdaloid structure; Animal Model; Animals; Behavior; Behavioral; Binding; Bioinformatics; Biological Markers; Brain; Candidate Disease Gene; Caregivers; Cells; Chronic; Data; Depressed mood; Development; Disease; Disease model; Elderly; Elements; Exposure to; Functional disorder; Future; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Glucocorticoids; Hepatitis C; Hepatitis C Therapy; Heterogeneity; Human; Hybrids; Inbred BALB C Mice; Individual; Inflammation; Inflammatory; Interferon-alpha; Interferons; Interleukin-6; Investigation; Literature; Lymphocyte; Major Depressive Disorder; Measures; Mental Depression; Messenger RNA; Mitogens; Molecular; Molecular Target; Mononuclear; Mus; Neurotic Disorders; Overlapping Genes; Pathway Analysis; Pathway interactions; Patients; Pattern; Peripheral Blood Mononuclear Cell; Physiological; Prevalence; Preventive Intervention; Prospective Studies; Protein Kinase; Recruitment Activity; Research Design; Response Elements; Risk; Sleep; Specific qualifier value; Symptoms; System; Techniques; Testing; Time; Tissues; Transcript; base; behavior test; biosignature; cytokine; design; disability; disorder subtype; high risk; innovation; interferon alfacon-1; member; mouse model; new technology; promoter; prospective; response; transcription factor; transcriptomics; translational approach

DESCRIPTION (provided by applicant): We are examining the major depression (MDD) that occurs during exposure to elevated levels of inflammatory cytokines, and specifically focusing on the MDD that develops during interferon-alpha (IFN-a) therapy (IFN-MDD). Because hepatitis C is very prevalent and the primary treatment is IFN-a-based, IFN-MDD is a common disorder. Because IFN-MDD develops within the few months of IFN-a treatment, it is a tractable condition for prospective study, and may be a good target for preventive intervention if those most vulnerable can be identified. A potential advantage is that a homologous set of behaviors can also be induced in IFN-treated mice. Our preliminary studies (i) support a growing literature that IFN-MDD shares many homologies with other MDD types and (ii) find that the whole genome transcriptome from mononuclear cells may be able to predict who is vulnerable to developing IFN-MDD and who is not. These results have identified the mitogen-associated protein kinase (MAPK) pathway as potentially being associated with this vulnerability. The next step that we propose is to determine mRNA biomarkers for IFN-MDD -- using Affymetrix microarrays to prospectively examine mRNA transcriptomes in humans receiving IFN-a-based therapy. In concert, we also intend to develop an animal platform as a translational approach for verifying molecular biomarker transcription patterns - of potential value for causally testing some of the biomarker pathways found in human IFN-MDD. For this, we propose to examine the mRNA transcriptomes and behaviors of mice treated with a behaviorally active human-mouse consensus IFN-a. The data generated by this 2-year study will guide our systematic next steps, which includes a more targeted and statistically powered investigation of the micro-array-identified pathways. PUBLIC HEALTH RELEVANCE: Delineating vulnerability to major depression is important for designing preventive interventions. We are thus examining non-depressed adult people at high risk for depression - because they are prescribed interferon-alpha (IFN-a) for hepatitis C. We are determining whether differences in various genes predict who gets depressed. To refine an animal model for examining these genes, we are also examining at the same time mice who are treated with IFN-a to examine what genes are turned on during IFN-a treatment.

描述（由申请人提供）：我们正在检查在暴露于升高水平的炎症细胞因子期间发生的重度抑郁症（MDD），并特别关注干扰素-α（IFN-a）治疗期间发生的MDD（IFN-MDD）。由于丙型肝炎非常普遍，并且主要治疗方法是以 IFN-a 为基础，因此 IFN-MDD 是一种常见疾病。由于 IFN-MDD 是在 IFN-a 治疗后的几个月内发生的，因此对于前瞻性研究而言，这是一种易于处理的疾病，如果能够确定最脆弱的人群，则可能成为预防性干预的良好目标。一个潜在的优势是，在 IFN 治疗的小鼠中也可以诱导出一组同源的行为。我们的初步研究 (i) 支持越来越多的文献表明 IFN-MDD 与其他 MDD 类型具有许多同源性，并且 (ii) 发现单核细胞的全基因组转录组可能能够预测谁容易患 IFN-MDD，谁不易患 IFN-MDD。这些结果已确定丝裂原相关蛋白激酶 (MAPK) 途径可能与此漏洞相关。我们建议的下一步是确定 IFN-MDD 的 mRNA 生物标志物——使用 Affymetrix 微阵列前瞻性地检查接受 IFN-α 治疗的人类的 mRNA 转录组。同时，我们还打算开发一个动物平台作为验证分子生物标志物转录模式的翻译方法 - 对于因果测试一些具有潜在价值 人类 IFN-MDD 中发现的生物标志物途径。为此，我们建议检查用行为活跃的人鼠共识 IFN-a 治疗的小鼠的 mRNA 转录组和行为。这项为期两年的研究产生的数据将指导我们系统性的后续步骤，其中包括对微阵列识别的途径进行更有针对性和统计有力的调查。 公共卫生相关性：描述重度抑郁症的脆弱性对于设计预防性干预措施非常重要。因此，我们正在检查患有抑郁症高风险的非抑郁成年人 - 因为他们服用干扰素α（IFN-a）来治疗丙型肝炎。我们正在确定各种基因的差异是否可以预测谁会患上抑郁症。为了完善检查这些基因的动物模型，我们还同时检查接受 IFN-a 治疗的小鼠，以检查在 IFN-a 治疗期间哪些基因被打开。