Transcriptome association with inflammation-related major depression

描述(申请人提供)：我们正在研究暴露在炎性细胞因子水平升高时发生的严重抑郁(MDD)，特别是关注在干扰素-α(干扰素-α)治疗过程中出现的MDD(干扰素-MDD)。由于丙型肝炎非常普遍，主要治疗方法是以干扰素为基础的，干扰素-MDD是一种常见的疾病。因为干扰素-MDD是在干扰素-α治疗后的几个月内发生的，所以对于前瞻性研究来说，它是一种易于治疗的情况，如果能够确定最脆弱的人群，它可能是预防干预的良好靶点。一个潜在的优势是，在干扰素处理的小鼠中也可以诱导出一系列相同的行为。我们的初步研究(I)支持越来越多的文献，即干扰素-MDD与其他MDD类型有许多同源性，(Ii)发现来自单个核细胞的全基因组转录组可能能够预测谁容易患上干扰素-MDD，谁不是。这些结果已经确定丝裂原相关蛋白激酶(MAPK)通路可能与这一漏洞有关。我们建议的下一步是确定干扰素-MDD的信使核糖核酸生物标志物--使用Affymetrix微阵列前瞻性地检查接受基于干扰素的治疗的人的信使核糖核酸转录。同时，我们还打算开发一个动物平台，作为验证分子生物标记物转录模式的翻译方法-对于因果测试一些潜在的价值 在人类干扰素-MDD中发现的生物标记物途径。为此，我们建议检测用行为活性的人-鼠共识干扰素-a处理的小鼠的mRNA转录和行为。这项为期两年的研究产生的数据将指导我们系统的下一步行动，其中包括对微阵列识别的途径进行更有针对性和统计支持的调查。

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.