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: 8511838
• 负责人: FRANCIS E LOTRICH
• 金额: $ 18.47万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511838
• 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.

描述（由申请人提供）：我们正在研究在暴露于升高水平的炎性细胞因子期间发生的重度抑郁症（MDD），并特别关注在干扰素-α（IFN-α）治疗期间发生的MDD（IFN-MDD）。由于丙型肝炎非常普遍，并且主要治疗是基于IFN-α的，因此IFN-MDD是一种常见疾病。由于IFN-MDD在IFN-a治疗的几个月内发展，因此它是前瞻性研究的易处理条件，并且如果可以识别出那些最脆弱的人，则可能是预防性干预的良好目标。一个潜在的优势是，在IFN处理的小鼠中也可以诱导一组同源的行为。我们的初步研究（i）支持越来越多的文献，即IFN-MDD与其他MDD类型具有许多同源性，（ii）发现单核细胞的全基因组转录组可能能够预测谁容易发生IFN-MDD，谁不会。这些结果已经确定有丝分裂原相关蛋白激酶（MAPK）通路可能与这种脆弱性有关。我们提出的下一步是确定IFN-MDD的mRNA生物标志物-使用Affyssin微阵列前瞻性地检查接受基于IFN-a的治疗的人的mRNA转录组。与此同时，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，这对因果测试一些 在人IFN-MDD中发现的生物标志物途径。为此，我们建议检查mRNA转录组和行为的小鼠治疗的行为活跃的人-小鼠共识IFN-α。这项为期2年的研究产生的数据将指导我们系统的下一步工作，其中包括对微阵列识别的途径进行更具针对性和统计学意义的调查。