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Genetic Regulation of Indoleamine-2,3-dioxygenase and Psychiatric Complications o

吲哚胺-2,3-双加氧酶的基因调控与精神并发症

基本信息

批准号：
7799933
负责人：
Gregory F Oxenkrug
金额：
$ 20.13万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-03 至 2011-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Genetic regulation of indoleamine-2,3-dioxygenase and psychiatric complications of IFN-alpha therapy Psychiatric complications are the often side effects of interferon-alpha (IFN-alpha) therapy of hepatitis C. Literature suggests that the up-regulation of indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway of tryptophan (TRY) metabolism, is responsible for the depression, anxiety, and psychosis observed during IFN-alpha therapy: a) activation of IDO shunts TRY metabolism to increased production of kynurenines, and away from synthesis of serotonin, the major substrate of antidepressant action; and b) kynurenine metabolites have anxiogenic and psychotomimetic effects. IDO is transcriptionally induced by pro-inflammatory cytokines. IFN-alpha stimulates IDO activity and production of IFN-gamma (IFNG) (the strongest transcriptional inducer of IDO), and of tumor necrosis factor-alpha (TNF-alpha) that amplifies IFNG-induced IDO expression. IFNG (+874) (T/A) and TNF-alpha(-308) (A/G) genotypes might predetermine the level of IFNG and TNF-alpha production, and, consequently, the degree of IDO activity and the frequency of psychiatric complications associated with IFN-alpha treatment. We suggest that combination of the high promoter T of IFNG (+874) with the high promoter A of TNF-alpha (-308) alleles might result in "super-induction" of IDO, and, therefore, in increased risk of psychiatric complications in IFN-alpha treated patients. Our working hypothesis is that individuals possessing a combination of high promoter alleles of IFNG (TT+TA) and TNF-alpha (AA+AG) are more prevalent among IFN-alpha treated patients with psychiatric complications than in patients without psychiatric complications. We propose a cross-sectional retrospective study of IFNG (+874)(T/A) and TNF-alpha(-308) (A/G/) gene polymorphisms in hepatitis C patients with and without psychiatric complications in response to IFN-alpha treatment. The obtained data might justify further studies of association between genotypes, cytokines levels, IDO activity and psychiatric complications, and suggest new ways of prediction and treatment of psychiatric complications of IFN-alpha therapy of hepatitis C and other IFN-alpha treated conditions, e.g., cancer, amyotrophic lateral sclerosis and multiple sclerosis. PUBLIC HEALTH RELEVANCE: The proposed study aims to investigate whether analysis of cytokine gene polymorphisms might help to identify hepatitis C patients with high risk of developing psychiatric complications in response to IFN-alpha therapy

描述（由申请人提供）：遗传调控吲哚胺-2,3-双加氧酶及ifn - α治疗的精神并发症精神并发症是丙型肝炎干扰素- α (ifn - α)治疗的常见副作用。文献表明，吲哚胺-2,3-双加氧酶（IDO）是色氨酸（TRY）代谢的犬尿氨酸途径的限制性酶，IDO的上调是ifn - α治疗期间观察到的抑郁、焦虑和精神病的原因。a) IDO的激活使TRY代谢增加犬尿胺的产生，远离抗抑郁作用的主要底物血清素的合成；b)犬尿氨酸代谢物具有致焦虑和拟精神作用。IDO是由促炎细胞因子转录诱导的。ifn - α刺激IDO活性和ifn - γ （IDO最强的转录诱导性因子）和肿瘤坏死因子- α (tnf - α)的产生，而ifn - α可放大IFNG诱导的IDO表达。IFNG (+874) （T/A）和tnf - α (-308) （A/G）基因型可能预先确定IFNG和tnf - α产生的水平，因此，IDO活性程度和与ifn - α治疗相关的精神并发症的频率。我们认为，IFNG的高启动子T（+874）与tnf - α(-308)等位基因的高启动子A的结合可能导致IDO的“超诱导”，因此，ifn - α治疗的患者出现精神并发症的风险增加。我们的工作假设是，拥有IFNG （TT+TA）和tnf - α (AA+AG)高启动子等位基因组合的个体在ifn - α治疗的精神并发症患者中比在没有精神并发症的患者中更普遍。我们建议对ifn - α治疗后伴有或不伴有精神并发症的丙型肝炎患者的IFNG (+874)（T/ a）和tnf - α (-308) （a /G/）基因多态性进行横断面回顾性研究。获得的数据可能为进一步研究基因型、细胞因子水平、IDO活性与精神并发症之间的关系提供依据，并为ifn - α治疗丙型肝炎和其他ifn - α治疗的疾病（如癌症、肌萎缩性侧索硬化症和多发性硬化症）的精神并发症的预测和治疗提供新的方法。公共卫生相关性：拟议的研究旨在调查细胞因子基因多态性分析是否有助于识别ifn - α治疗后出现精神并发症的高风险丙型肝炎患者